Journal of Clinical Neuroscience xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Olfactory abnormalities in temporal lobe epilepsy M. Desai ⇑, J.B. Agadi, N. Karthik, S. Praveenkumar, A.B. Netto Department of Neurology, Pradhan Mantri Swasthya Suraksha Yojana Super-Speciality Hospital, Bangalore Medical College and Research Institute, First Floor, Krishna Rajendra Road, Fort, Bangalore, Karnataka 560004, India
a r t i c l e
i n f o
Article history: Received 4 July 2014 Accepted 8 March 2015 Available online xxxx Keywords: Smell identification Temporal lobe epilepsy University of Pennsylvania smell identification test
a b s t r a c t We studied olfactory function in a cohort of 25 temporal lobe epilepsy (TLE) patients and 25 healthy controls. Our objectives were to measure olfactory acuity in patients with right, left or bilateral TLE and compare them with age and sex matched controls, and to correlate olfactory acuity with duration of seizure, baseline seizure control and the number of drugs used. Olfactory impairment is common in neurological disorders and dysfunction of the temporo-limbic neural substrates involved in olfactory perception is noted in TLE. We measured olfactory acuity in 25 patients with TLE, nine with right, 10 with left and six with bilateral temporal lobe seizure activity, and compared them to the controls. Odor identification was assessed using the University of Pennsylvania Smell Identification Test (UPSIT) which is a 40 item olfactory test used to diagnose olfactory deficits. Our results showed that patients with TLE exhibited significant impairment in UPSIT performance compared to the controls. There was no significant difference in scores between the right and left TLE patients. The severity of olfactory impairment did not correlate with the duration of seizures, baseline seizure control and number of drugs used. We concluded that significant olfactory impairment is seen in both right and left TLE patients, unrelated to the duration and baseline frequency of seizures or drugs used. Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction Temporal lobe epilepsy (TLE) is associated with a characteristic semiology of seizures, termed psychomotor seizures, and ictal epileptic discharges arising from mesial, and less commonly, lateral or neocortical temporal lobe regions. It may serve as a model for lateralized brain impairment, as brain function governed by temporal lobe structures (memory and language) shows differential impairment depending on the side of the epileptic focus [1]. The importance of temporal lobe structures in human olfactory function has been recognized since the nineteenth century with the observation that olfactory auras could precede paroxystic seizures in epileptic patients [2]. Many investigators then tried to determine the influence of TLE on olfactory function using behavioural studies. Olfactory sensitivity, assessed using detection or recognition threshold measurements, was usually reported to be in the normal range compared with healthy controls [3–6]. In contrast, a wide variety of tasks (for example, odour matching, discrimination, short and long term recognition, identification and naming) highlighted consistent deficits in higher olfactory functions [3–9]. Factors such as stimulation type (monorhinal or ⇑ Corresponding author. Tel.: +91 9964403657. E-mail address: [email protected] (M. Desai).
birhinal), stimulated nostril side (ipsi or controlaterally to the epileptogenic focus), and odorant nameability appeared to be determining factors in patient performance. Due to the methodological differences between various studies, it is difficult to determine deficit patterns in relation to the epileptogenic focus location, duration and frequency of seizures and the population studied. We studied olfactory acuity in a selected group of TLE patients from South India using the University of Pennsylvania Smell Identification Test (UPSIT) kits. The objective of our study was to measure olfactory acuity in patients with right, left and bilateral TLE and compare that with healthy controls, and to correlate olfactory acuity with the duration of seizures, baseline seizure control and number of drugs used. 2. Materials and methods 2.1. Sample This study was conducted in the Department of Neurology in a tertiary care center in South India. Twenty-five patients with TLE, nine with right, 10 with left and six with bilateral temporal lobe seizure activity participated in the study. Their performance was compared with 25 healthy age, sex and education matched controls.
http://dx.doi.org/10.1016/j.jocn.2015.03.035 0967-5868/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Desai M et al. Olfactory abnormalities in temporal lobe epilepsy. J Clin Neurosci (2015), http://dx.doi.org/10.1016/ j.jocn.2015.03.035
2
M. Desai et al. / Journal of Clinical Neuroscience xxx (2015) xxx–xxx
Patients with other risk factors for hyposmia, including upper respiratory infection, head injury, liver, renal and thyroid abnormalities, and other neurological and psychiatric disorders were excluded from the study. Diagnosis of TLE and focus lateralization were based on a comprehensive assessment which included seizure semiology obtained from eye witnesses or video recordings, interictal electroencephalogram (EEG) abnormalities in all, ictal video EEG findings in six patients and routine visual MRI analysis, the protocol of which included T1 and T2-weighted and fluid-attenuated inversion recovery sequences in axial and coronal planes. The clinical diagnosis of TLE was based on the International League Against Epilepsy Commission Report from 2004 as follows: (1) seizure semiology consistent with TLE with abdominal, epigastric, psychic, or autonomic auras followed by behavioral arrest, progressive alteration of consciousness, oroalimentary, and manual automatisms; (2) interictal EEG and/or video EEG showing temporal spikes; (3) no lesions other than increased T2-weighted signal and/or atrophy in hippocampal formation identified by MRI. 2.2. Cross sectional case-control study design Odor identification was assessed with the UPSIT [10]. This test uses encapsulated micro odorants which are released on scratching using a pencil on a standardized odor impregnated test booklet. Patients are asked to identify the odor from four choices provided for each question. The kit consists of four booklets, each containing ten questions. Hence, a maximum score is 40. This forced-choice standardized test is sensitive to a wide variety of olfactory defects [11]. Patients were clinically stable at the time of olfactory testing, were medicated with standard doses of antiepileptic drugs and did not show any effects of recent seizures such as postictal confusion.
Table 1 TLE patient and healthy control demographics Demographics
TLE patients (n = 25)
Controls (n = 25)
Age, mean years (range)
28.2 (18–47)
28.8 (18–47)
Sex Male Female Education, mean years (range)
15 10 11.6 (4–16)
15 10 12.08 (5–16)
Smoking status Current smoker Past smoker Never smoked
0 3 22
0 4 21
TLE = temporal lobe epilepsy.
Table 2 TLE patient clinical characteristics Characteristic
n = 25
Lateralization based on EEG discharges, n (M, F) Right Left Bilateral
9 (4, 5) 10 (7, 3) 6 (4, 2)
Seizure frequency per month over the past 2 years, mean (range) Duration of seizures, mean years (range) Antiepileptic drug use, n One drug Two drugs Three drugs MRI brain abnormalities, n Right MTS Left MTS Bilateral MTS Other lesions Normal
2.4 (0.1–30) 12.08 (2–32) 9 12 4 7 8 2 2 7
EEG = electroencephalogram, F = female, M = male, MTS = mesial temporal sclerosis, TLE = temporal lobe epilepsy.
2.3. Statistical analyses Data are expressed as the mean, median, standard error and range. Parametric and non-parametric comparisons were assessed by Levene’s test for equality of variance and one way analysis of variance. Pearson’s product-moment correlations were used to assess the relationships between concomitant variables. Statistical analyses were carried out using the SPSS software (version 20.0; IBM Corporation, Armonk, NY, USA). All variables were two tail tested and differences with p 6 0.05 were considered significant. 3. Results The TLE patients and healthy controls did not differ with regard to age (F[1,48] = 4.03; p = 0.18), sex (chi-squared = 2.64; degrees of freedom [df] = 2; p = 0.80), education (F[1,48] = 2.81; p = 0.095) or smoking status (chi-squared = 3.2; df = 4; p = 0.16). The patient and control demographics are summarized in Table 1, and clinical characteristics in Table 2. The performances (UPSIT scores) for birhinal olfactory identification (mean ± standard error of mean) were as follows: patients with TLE (22.08 ± 0.868), including those with right TLE (21.33 ± 1.0), left TLE (21.4 ± 1.75) and bilateral TLE (24.33 ± 1.43), and the healthy controls (27.28 ± 0.567; Fig. 1). With regard to odor perception, Levene’s test for the quality of variance revealed a major effect of TLE diagnosis on UPSIT performance (F[1,48] = 2.28; p = 0.0001) but no effect on the duration of seizures (p = 0.613), baseline seizure frequency (p = 0.149) and the number of drugs used (p = 0.149; Fig. 2). The UPSIT scores of
Fig. 1. Box plot comparing the distribution of the University of Pennsylvania Smell Identification Test (UPSIT) scores among: (a) temporal lobe epilepsy (TLE) patients versus healthy control group and (b) right TLE versus left TLE patients. This figure is available in colour at www.sciencedirect.com.
Please cite this article in press as: Desai M et al. Olfactory abnormalities in temporal lobe epilepsy. J Clin Neurosci (2015), http://dx.doi.org/10.1016/ j.jocn.2015.03.035
M. Desai et al. / Journal of Clinical Neuroscience xxx (2015) xxx–xxx
3
Fig. 2. Scatter plot comparing the University of Pennsylvania Smell Identification Test (UPSIT) scores of temporal lobe epilepsy (TLE) patients with (a) average seizure frequency per month, (b) duration of seizures in years, and (c) number of antiepileptic drugs (AED) used. This figure is available in colour at www.sciencedirect.com.
patients with right and left TLE did not differ significantly (F[1,17] = 1.072; p = 0.36; Fig. 1). Among the odors, peanut was identified by most TLE patients followed by onion, grass, mint and menthol. The least identified were pickle, lime and cheese. Among the controls, bubble gum, peanut and lilac were most identified and ginger and cheese were least identified. Most of the low scoring odors among the TLE patients were better identified by the controls, and the difference was most significant for smoke, cedar, soap and clove (Fig. 3).
4. Discussion Olfaction is subserved by inferior frontal and adjacent mesial temporal brain regions, specifically the olfactory trigone, prepiriform cortex, entorhinal cortex, and amygdala. It has been described that primary olfactory processing occurs in areas of the olfactory bulb, piriform, and entorhinal cortex, whereas secondary processing occurs in orbitofrontal, mesial temporal, thalamic, and hypothalamic regions [9,12,13]. The olfactory
Please cite this article in press as: Desai M et al. Olfactory abnormalities in temporal lobe epilepsy. J Clin Neurosci (2015), http://dx.doi.org/10.1016/ j.jocn.2015.03.035
4
M. Desai et al. / Journal of Clinical Neuroscience xxx (2015) xxx–xxx
Fig. 3. Bar charts showing the number of temporal lobe epilepsy (TLE) patients and healthy controls who correctly identified various smells in the University of Pennsylvania Smell Identification Test (UPSIT) kit.
system is unique in that, unlike other sensory systems, the primary projections are largely ipsilateral and therefore may provide a unique opportunity to probe for lateralized deficits in hemispheric processing of olfactory information. Previous studies have found impaired odor discrimination upon monorhinic [3] and birhinic administration [7,8,14] in patients with temporal and frontal lobe epilepsy, but not in patients with epilepsy arising from outside the fronto-temporal regions [14]. In addition, studies have shown impairment of olfactory identification [3] and discrimination [15] upon monorhinic presentation ipsilateral to the side of temporal lobectomy. Our findings reveal that patients with TLE are impaired in olfactory identification (acuity) when compared with matched, healthy controls. We found no differential deficit in performance between right or left TLE patients, with both groups being significantly impaired relative to the controls. These data support the notion that olfactory processing involves bihemispheric regions that are equally critical. Olfactory perception was preserved in all patients and controls. Data obtained from TLE patients who had undergone a surgical excision of the epileptogenic focus suggest that there might be some degree of specialization of the right temporal lobe for odor processing [3,5,7,14–17]. Conversely, Hudrey et al. [18] observed that left TLE patients were more impaired in olfactory identification and discrimination than those with right sided TLE. Zatorre et al. [15] also observed decreased performance in odor discrimination, which was higher in patients with excision of the left temporal lobe stimulated via the left nostril than in patients with excision of the right temporal lobe stimulated via the right nostril. However, this difference was not statistically tested. Studies have shown a relationship between epileptogenic lesions in the left hemisphere and the affective content of verbal memory [19], the adoption of a more liberal decision criterion in recognition memory for verbal and visuo-spatial materials [20] and depression [21]. Finally, the data can be related to neuroimaging studies that indicate a strong involvement of left cerebral structures (amygdala, temporal pole, subcallosal, orbitofrontal and superior frontal gyri)
in emotional processing, [22] which are in close association with olfactory regions. Olfactory function in TLE was previously evaluated by several modes of stimulus delivery, but one study by Kohler et al. [1] used the standard UPSIT kits for olfactory assessment and reported impaired olfactory performance in TLE patients, with right TLE showing significantly lower scores than left. The results of our study confirm the previous findings of impaired olfactory acuity in TLE patients, but we found no difference in olfactory performance of right versus left TLE. This offers indirect evidence for the role of the bilateral temporo-limbic neural substrates in olfactory processing. The severity of olfactory impairment did not correlate with the duration of seizure or baseline seizure control, which was assessed based on the average seizure frequency per month over the past 2 years (Fig. 2). Patients with TLE were treated with single and combination regimens of antiepileptic drugs and their olfactory impairment did not correlate with the number of drugs used (Fig. 2). The impact of medication on olfactory function has received considerable attention in the literature. The published empirical data concerning medication effects on olfaction in any neurologic or neuropsychiatric disorder have largely been negative [1]. We also found that olfactory dysfunction spanned most of the odors and there was a significant difference between patients and controls in 14 out of 40 odors studied with smoke, cedar, soap and clove being the most discriminating in our study. There are few sytematic studies on quantitative impairment of olfactory performance in TLE and to the best of our knowledge, no studies have been reported from India to date. The small sample size is a limitation of this study, and although subjects had prior experience with most of the odors in UPSIT, a few of them were novel to them due to cultural differences. A standardized Indian form of the UPSIT would be useful for future studies. Our findings will assist in educating TLE patients about the olfactory discriminatory deficit and its consequences, which remain unrelated to seizure duration or adequate control with drugs. The results may further guide research towards recognition
Please cite this article in press as: Desai M et al. Olfactory abnormalities in temporal lobe epilepsy. J Clin Neurosci (2015), http://dx.doi.org/10.1016/ j.jocn.2015.03.035
M. Desai et al. / Journal of Clinical Neuroscience xxx (2015) xxx–xxx
of the bilateral rather than unilateral temporo-limic structures that are involved and their role in olfactory processing. 5. Conclusion The results of this study suggest that smell identification and discrimination is impaired in TLE patients. Olfactory loss is similar in right and left TLE, indicating a role of bihemispheric structures in smell perception. Olfactory impairment is not related to the duration of seizure, baseline seizure control or the number of drugs used. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. References [1] Kohler CG, Moberg PJ, Gur RE, et al. Olfactory dysfunction in schizophrenia and temporal lobe epilepsy. Neuropsychiatry Neuropsychol Behav Neurol 2001;14:83–8. [2] Jackson JH, Stewart P. Epileptic attacks with a warning of a crude sensation of smell and with the intellectual aura (dreamy state) in a patient who had symptoms pointing to gross organic disease of the right temporo-sphenoidal lobe. Brain 1899;22:534–49. [3] Eskenazi B, Cain WS, Novelly RA, et al. Olfactory functioning in temporal lobectomy patients. Neuropsychologia 1983;21:365–74. [4] Martinez BA, Cain WS, De Wijk RA, et al. Olfactory functioning before and after temporal lobe resection for intractable seizures. Neuropsychology 1993;7:351–63. [5] Jones-Gotman M, Zatorre RJ, Cendes F, et al. Contribution of medial versus lateral temporal lobe structures to human odour identification. Brain 1997;120:1845–56.
5
[6] Savic I, Bookheimer SY, Fried I, et al. Olfactory bedside tests: a simple approach to identify temporo-orbitofrontal dysfunction. Arch Neurol 1997;54:162–8. [7] Abraham A, Mathai KV. The effect of right temporal lobe lesions on matching of smells. Neuropsychologia 1983;21:277–81. [8] Carroll B, Richardson JT, Thompson P. Olfactory information processing and temporal lobe epilepsy. Brain Cogn 1993;22:230–43. [9] West SE, Doty RL. Influence of epilepsy and temporal lobe resection on olfactory function. Epilepsia 1995;36:531–42. [10] Doty RL, Shaman P, Dann M. Development of the University of Pennsylvania smell identification test: a standardized microencapsulated test of olfactory function. Physiol Behav 1984;32:489–502. [11] Doty RL. Studies of olfactory dysfunction in major neurological disorders. Adv Biosci 1994;93:593–602. [12] Tagaki SF. Dual systems for sensory olfactory processing in higher primates. Trends Neurosci 1979;2:313–5. [13] Price JL, Carmichael T, Carnes KM, et al. Olfactory input to the prefrontal cortex. In: Davis JL, Eichenbaum H, editors. Olfaction. Cambridge, MA: MIT Press; 1991. p. 101–20. [14] Jones-Gotman M, Zatorre RJ. Olfactory identification deficits in patients with focal cerebral excisions. Neuropsychology 1988;26:387–400. [15] Zatorre RJ, Jones-Gotman M. Human olfactory discrimination after unilateral frontal or temporal lobectomy. Brain 1991;114:71–84. [16] Rausch R, Serafetinides EA. Specific alterations of olfactory function in humans with temporal lobe lesions. Nature 1975;255:557–8. [17] Rausch R, Serafetinides EA, Crandall PH. Olfactory memory in patients with anterior temporal lobectomy. Cortex 1977;13:445–52. [18] Hudry J, Perrin F, Ryvlin P, et al. Olfactory short-term memory and related amygdala recordings in patients with temporal lobe epilepsy. Brain 2003;126:1851–63. [19] Burton LA, Gilliam D, Flynn S, et al. Affective verbal memory in patients with temporal lobe epilepsy. Appl Neuropsychol 1999;6:115–20. [20] Glosser G, Deutsch GK, Cole LC, et al. Differential lateralization of memory discrimination and response bias in temporal lobe epilepsy patients. J Int Neuropsychol Soc 1998;4:502–11. [21] Mendez MF, Taylor JL, Doss RC, et al. Depression in secondary epilepsy: relation to lesion laterality. J Neurol Neurosurg Psychiatry 1994;57:232–3. [22] Royet JP, Zald D, Versace R, et al. Emotional responses to pleasant and unpleasant olfactory, visual, and auditory stimuli: a positron emission tomography study. J Neurosci 2000;20:7752–9.
Please cite this article in press as: Desai M et al. Olfactory abnormalities in temporal lobe epilepsy. J Clin Neurosci (2015), http://dx.doi.org/10.1016/ j.jocn.2015.03.035
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Olfactory abnormalities in temporal lobe epilepsy M. Desai ⇑, J.B. Agadi, N. Karthik, S. Praveenkumar, A.B. Netto Department of Neurology, Pradhan Mantri Swasthya Suraksha Yojana Super-Speciality Hospital, Bangalore Medical College and Research Institute, First Floor, Krishna Rajendra Road, Fort, Bangalore, Karnataka 560004, India
a r t i c l e
i n f o
Article history: Received 4 July 2014 Accepted 8 March 2015 Available online xxxx Keywords: Smell identification Temporal lobe epilepsy University of Pennsylvania smell identification test
a b s t r a c t We studied olfactory function in a cohort of 25 temporal lobe epilepsy (TLE) patients and 25 healthy controls. Our objectives were to measure olfactory acuity in patients with right, left or bilateral TLE and compare them with age and sex matched controls, and to correlate olfactory acuity with duration of seizure, baseline seizure control and the number of drugs used. Olfactory impairment is common in neurological disorders and dysfunction of the temporo-limbic neural substrates involved in olfactory perception is noted in TLE. We measured olfactory acuity in 25 patients with TLE, nine with right, 10 with left and six with bilateral temporal lobe seizure activity, and compared them to the controls. Odor identification was assessed using the University of Pennsylvania Smell Identification Test (UPSIT) which is a 40 item olfactory test used to diagnose olfactory deficits. Our results showed that patients with TLE exhibited significant impairment in UPSIT performance compared to the controls. There was no significant difference in scores between the right and left TLE patients. The severity of olfactory impairment did not correlate with the duration of seizures, baseline seizure control and number of drugs used. We concluded that significant olfactory impairment is seen in both right and left TLE patients, unrelated to the duration and baseline frequency of seizures or drugs used. Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction Temporal lobe epilepsy (TLE) is associated with a characteristic semiology of seizures, termed psychomotor seizures, and ictal epileptic discharges arising from mesial, and less commonly, lateral or neocortical temporal lobe regions. It may serve as a model for lateralized brain impairment, as brain function governed by temporal lobe structures (memory and language) shows differential impairment depending on the side of the epileptic focus [1]. The importance of temporal lobe structures in human olfactory function has been recognized since the nineteenth century with the observation that olfactory auras could precede paroxystic seizures in epileptic patients [2]. Many investigators then tried to determine the influence of TLE on olfactory function using behavioural studies. Olfactory sensitivity, assessed using detection or recognition threshold measurements, was usually reported to be in the normal range compared with healthy controls [3–6]. In contrast, a wide variety of tasks (for example, odour matching, discrimination, short and long term recognition, identification and naming) highlighted consistent deficits in higher olfactory functions [3–9]. Factors such as stimulation type (monorhinal or ⇑ Corresponding author. Tel.: +91 9964403657. E-mail address: [email protected] (M. Desai).
birhinal), stimulated nostril side (ipsi or controlaterally to the epileptogenic focus), and odorant nameability appeared to be determining factors in patient performance. Due to the methodological differences between various studies, it is difficult to determine deficit patterns in relation to the epileptogenic focus location, duration and frequency of seizures and the population studied. We studied olfactory acuity in a selected group of TLE patients from South India using the University of Pennsylvania Smell Identification Test (UPSIT) kits. The objective of our study was to measure olfactory acuity in patients with right, left and bilateral TLE and compare that with healthy controls, and to correlate olfactory acuity with the duration of seizures, baseline seizure control and number of drugs used. 2. Materials and methods 2.1. Sample This study was conducted in the Department of Neurology in a tertiary care center in South India. Twenty-five patients with TLE, nine with right, 10 with left and six with bilateral temporal lobe seizure activity participated in the study. Their performance was compared with 25 healthy age, sex and education matched controls.
http://dx.doi.org/10.1016/j.jocn.2015.03.035 0967-5868/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Desai M et al. Olfactory abnormalities in temporal lobe epilepsy. J Clin Neurosci (2015), http://dx.doi.org/10.1016/ j.jocn.2015.03.035
2
M. Desai et al. / Journal of Clinical Neuroscience xxx (2015) xxx–xxx
Patients with other risk factors for hyposmia, including upper respiratory infection, head injury, liver, renal and thyroid abnormalities, and other neurological and psychiatric disorders were excluded from the study. Diagnosis of TLE and focus lateralization were based on a comprehensive assessment which included seizure semiology obtained from eye witnesses or video recordings, interictal electroencephalogram (EEG) abnormalities in all, ictal video EEG findings in six patients and routine visual MRI analysis, the protocol of which included T1 and T2-weighted and fluid-attenuated inversion recovery sequences in axial and coronal planes. The clinical diagnosis of TLE was based on the International League Against Epilepsy Commission Report from 2004 as follows: (1) seizure semiology consistent with TLE with abdominal, epigastric, psychic, or autonomic auras followed by behavioral arrest, progressive alteration of consciousness, oroalimentary, and manual automatisms; (2) interictal EEG and/or video EEG showing temporal spikes; (3) no lesions other than increased T2-weighted signal and/or atrophy in hippocampal formation identified by MRI. 2.2. Cross sectional case-control study design Odor identification was assessed with the UPSIT [10]. This test uses encapsulated micro odorants which are released on scratching using a pencil on a standardized odor impregnated test booklet. Patients are asked to identify the odor from four choices provided for each question. The kit consists of four booklets, each containing ten questions. Hence, a maximum score is 40. This forced-choice standardized test is sensitive to a wide variety of olfactory defects [11]. Patients were clinically stable at the time of olfactory testing, were medicated with standard doses of antiepileptic drugs and did not show any effects of recent seizures such as postictal confusion.
Table 1 TLE patient and healthy control demographics Demographics
TLE patients (n = 25)
Controls (n = 25)
Age, mean years (range)
28.2 (18–47)
28.8 (18–47)
Sex Male Female Education, mean years (range)
15 10 11.6 (4–16)
15 10 12.08 (5–16)
Smoking status Current smoker Past smoker Never smoked
0 3 22
0 4 21
TLE = temporal lobe epilepsy.
Table 2 TLE patient clinical characteristics Characteristic
n = 25
Lateralization based on EEG discharges, n (M, F) Right Left Bilateral
9 (4, 5) 10 (7, 3) 6 (4, 2)
Seizure frequency per month over the past 2 years, mean (range) Duration of seizures, mean years (range) Antiepileptic drug use, n One drug Two drugs Three drugs MRI brain abnormalities, n Right MTS Left MTS Bilateral MTS Other lesions Normal
2.4 (0.1–30) 12.08 (2–32) 9 12 4 7 8 2 2 7
EEG = electroencephalogram, F = female, M = male, MTS = mesial temporal sclerosis, TLE = temporal lobe epilepsy.
2.3. Statistical analyses Data are expressed as the mean, median, standard error and range. Parametric and non-parametric comparisons were assessed by Levene’s test for equality of variance and one way analysis of variance. Pearson’s product-moment correlations were used to assess the relationships between concomitant variables. Statistical analyses were carried out using the SPSS software (version 20.0; IBM Corporation, Armonk, NY, USA). All variables were two tail tested and differences with p 6 0.05 were considered significant. 3. Results The TLE patients and healthy controls did not differ with regard to age (F[1,48] = 4.03; p = 0.18), sex (chi-squared = 2.64; degrees of freedom [df] = 2; p = 0.80), education (F[1,48] = 2.81; p = 0.095) or smoking status (chi-squared = 3.2; df = 4; p = 0.16). The patient and control demographics are summarized in Table 1, and clinical characteristics in Table 2. The performances (UPSIT scores) for birhinal olfactory identification (mean ± standard error of mean) were as follows: patients with TLE (22.08 ± 0.868), including those with right TLE (21.33 ± 1.0), left TLE (21.4 ± 1.75) and bilateral TLE (24.33 ± 1.43), and the healthy controls (27.28 ± 0.567; Fig. 1). With regard to odor perception, Levene’s test for the quality of variance revealed a major effect of TLE diagnosis on UPSIT performance (F[1,48] = 2.28; p = 0.0001) but no effect on the duration of seizures (p = 0.613), baseline seizure frequency (p = 0.149) and the number of drugs used (p = 0.149; Fig. 2). The UPSIT scores of
Fig. 1. Box plot comparing the distribution of the University of Pennsylvania Smell Identification Test (UPSIT) scores among: (a) temporal lobe epilepsy (TLE) patients versus healthy control group and (b) right TLE versus left TLE patients. This figure is available in colour at www.sciencedirect.com.
Please cite this article in press as: Desai M et al. Olfactory abnormalities in temporal lobe epilepsy. J Clin Neurosci (2015), http://dx.doi.org/10.1016/ j.jocn.2015.03.035
M. Desai et al. / Journal of Clinical Neuroscience xxx (2015) xxx–xxx
3
Fig. 2. Scatter plot comparing the University of Pennsylvania Smell Identification Test (UPSIT) scores of temporal lobe epilepsy (TLE) patients with (a) average seizure frequency per month, (b) duration of seizures in years, and (c) number of antiepileptic drugs (AED) used. This figure is available in colour at www.sciencedirect.com.
patients with right and left TLE did not differ significantly (F[1,17] = 1.072; p = 0.36; Fig. 1). Among the odors, peanut was identified by most TLE patients followed by onion, grass, mint and menthol. The least identified were pickle, lime and cheese. Among the controls, bubble gum, peanut and lilac were most identified and ginger and cheese were least identified. Most of the low scoring odors among the TLE patients were better identified by the controls, and the difference was most significant for smoke, cedar, soap and clove (Fig. 3).
4. Discussion Olfaction is subserved by inferior frontal and adjacent mesial temporal brain regions, specifically the olfactory trigone, prepiriform cortex, entorhinal cortex, and amygdala. It has been described that primary olfactory processing occurs in areas of the olfactory bulb, piriform, and entorhinal cortex, whereas secondary processing occurs in orbitofrontal, mesial temporal, thalamic, and hypothalamic regions [9,12,13]. The olfactory
Please cite this article in press as: Desai M et al. Olfactory abnormalities in temporal lobe epilepsy. J Clin Neurosci (2015), http://dx.doi.org/10.1016/ j.jocn.2015.03.035
4
M. Desai et al. / Journal of Clinical Neuroscience xxx (2015) xxx–xxx
Fig. 3. Bar charts showing the number of temporal lobe epilepsy (TLE) patients and healthy controls who correctly identified various smells in the University of Pennsylvania Smell Identification Test (UPSIT) kit.
system is unique in that, unlike other sensory systems, the primary projections are largely ipsilateral and therefore may provide a unique opportunity to probe for lateralized deficits in hemispheric processing of olfactory information. Previous studies have found impaired odor discrimination upon monorhinic [3] and birhinic administration [7,8,14] in patients with temporal and frontal lobe epilepsy, but not in patients with epilepsy arising from outside the fronto-temporal regions [14]. In addition, studies have shown impairment of olfactory identification [3] and discrimination [15] upon monorhinic presentation ipsilateral to the side of temporal lobectomy. Our findings reveal that patients with TLE are impaired in olfactory identification (acuity) when compared with matched, healthy controls. We found no differential deficit in performance between right or left TLE patients, with both groups being significantly impaired relative to the controls. These data support the notion that olfactory processing involves bihemispheric regions that are equally critical. Olfactory perception was preserved in all patients and controls. Data obtained from TLE patients who had undergone a surgical excision of the epileptogenic focus suggest that there might be some degree of specialization of the right temporal lobe for odor processing [3,5,7,14–17]. Conversely, Hudrey et al. [18] observed that left TLE patients were more impaired in olfactory identification and discrimination than those with right sided TLE. Zatorre et al. [15] also observed decreased performance in odor discrimination, which was higher in patients with excision of the left temporal lobe stimulated via the left nostril than in patients with excision of the right temporal lobe stimulated via the right nostril. However, this difference was not statistically tested. Studies have shown a relationship between epileptogenic lesions in the left hemisphere and the affective content of verbal memory [19], the adoption of a more liberal decision criterion in recognition memory for verbal and visuo-spatial materials [20] and depression [21]. Finally, the data can be related to neuroimaging studies that indicate a strong involvement of left cerebral structures (amygdala, temporal pole, subcallosal, orbitofrontal and superior frontal gyri)
in emotional processing, [22] which are in close association with olfactory regions. Olfactory function in TLE was previously evaluated by several modes of stimulus delivery, but one study by Kohler et al. [1] used the standard UPSIT kits for olfactory assessment and reported impaired olfactory performance in TLE patients, with right TLE showing significantly lower scores than left. The results of our study confirm the previous findings of impaired olfactory acuity in TLE patients, but we found no difference in olfactory performance of right versus left TLE. This offers indirect evidence for the role of the bilateral temporo-limbic neural substrates in olfactory processing. The severity of olfactory impairment did not correlate with the duration of seizure or baseline seizure control, which was assessed based on the average seizure frequency per month over the past 2 years (Fig. 2). Patients with TLE were treated with single and combination regimens of antiepileptic drugs and their olfactory impairment did not correlate with the number of drugs used (Fig. 2). The impact of medication on olfactory function has received considerable attention in the literature. The published empirical data concerning medication effects on olfaction in any neurologic or neuropsychiatric disorder have largely been negative [1]. We also found that olfactory dysfunction spanned most of the odors and there was a significant difference between patients and controls in 14 out of 40 odors studied with smoke, cedar, soap and clove being the most discriminating in our study. There are few sytematic studies on quantitative impairment of olfactory performance in TLE and to the best of our knowledge, no studies have been reported from India to date. The small sample size is a limitation of this study, and although subjects had prior experience with most of the odors in UPSIT, a few of them were novel to them due to cultural differences. A standardized Indian form of the UPSIT would be useful for future studies. Our findings will assist in educating TLE patients about the olfactory discriminatory deficit and its consequences, which remain unrelated to seizure duration or adequate control with drugs. The results may further guide research towards recognition
Please cite this article in press as: Desai M et al. Olfactory abnormalities in temporal lobe epilepsy. J Clin Neurosci (2015), http://dx.doi.org/10.1016/ j.jocn.2015.03.035
M. Desai et al. / Journal of Clinical Neuroscience xxx (2015) xxx–xxx
of the bilateral rather than unilateral temporo-limic structures that are involved and their role in olfactory processing. 5. Conclusion The results of this study suggest that smell identification and discrimination is impaired in TLE patients. Olfactory loss is similar in right and left TLE, indicating a role of bihemispheric structures in smell perception. Olfactory impairment is not related to the duration of seizure, baseline seizure control or the number of drugs used. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. References [1] Kohler CG, Moberg PJ, Gur RE, et al. Olfactory dysfunction in schizophrenia and temporal lobe epilepsy. Neuropsychiatry Neuropsychol Behav Neurol 2001;14:83–8. [2] Jackson JH, Stewart P. Epileptic attacks with a warning of a crude sensation of smell and with the intellectual aura (dreamy state) in a patient who had symptoms pointing to gross organic disease of the right temporo-sphenoidal lobe. Brain 1899;22:534–49. [3] Eskenazi B, Cain WS, Novelly RA, et al. Olfactory functioning in temporal lobectomy patients. Neuropsychologia 1983;21:365–74. [4] Martinez BA, Cain WS, De Wijk RA, et al. Olfactory functioning before and after temporal lobe resection for intractable seizures. Neuropsychology 1993;7:351–63. [5] Jones-Gotman M, Zatorre RJ, Cendes F, et al. Contribution of medial versus lateral temporal lobe structures to human odour identification. Brain 1997;120:1845–56.
5
[6] Savic I, Bookheimer SY, Fried I, et al. Olfactory bedside tests: a simple approach to identify temporo-orbitofrontal dysfunction. Arch Neurol 1997;54:162–8. [7] Abraham A, Mathai KV. The effect of right temporal lobe lesions on matching of smells. Neuropsychologia 1983;21:277–81. [8] Carroll B, Richardson JT, Thompson P. Olfactory information processing and temporal lobe epilepsy. Brain Cogn 1993;22:230–43. [9] West SE, Doty RL. Influence of epilepsy and temporal lobe resection on olfactory function. Epilepsia 1995;36:531–42. [10] Doty RL, Shaman P, Dann M. Development of the University of Pennsylvania smell identification test: a standardized microencapsulated test of olfactory function. Physiol Behav 1984;32:489–502. [11] Doty RL. Studies of olfactory dysfunction in major neurological disorders. Adv Biosci 1994;93:593–602. [12] Tagaki SF. Dual systems for sensory olfactory processing in higher primates. Trends Neurosci 1979;2:313–5. [13] Price JL, Carmichael T, Carnes KM, et al. Olfactory input to the prefrontal cortex. In: Davis JL, Eichenbaum H, editors. Olfaction. Cambridge, MA: MIT Press; 1991. p. 101–20. [14] Jones-Gotman M, Zatorre RJ. Olfactory identification deficits in patients with focal cerebral excisions. Neuropsychology 1988;26:387–400. [15] Zatorre RJ, Jones-Gotman M. Human olfactory discrimination after unilateral frontal or temporal lobectomy. Brain 1991;114:71–84. [16] Rausch R, Serafetinides EA. Specific alterations of olfactory function in humans with temporal lobe lesions. Nature 1975;255:557–8. [17] Rausch R, Serafetinides EA, Crandall PH. Olfactory memory in patients with anterior temporal lobectomy. Cortex 1977;13:445–52. [18] Hudry J, Perrin F, Ryvlin P, et al. Olfactory short-term memory and related amygdala recordings in patients with temporal lobe epilepsy. Brain 2003;126:1851–63. [19] Burton LA, Gilliam D, Flynn S, et al. Affective verbal memory in patients with temporal lobe epilepsy. Appl Neuropsychol 1999;6:115–20. [20] Glosser G, Deutsch GK, Cole LC, et al. Differential lateralization of memory discrimination and response bias in temporal lobe epilepsy patients. J Int Neuropsychol Soc 1998;4:502–11. [21] Mendez MF, Taylor JL, Doss RC, et al. Depression in secondary epilepsy: relation to lesion laterality. J Neurol Neurosurg Psychiatry 1994;57:232–3. [22] Royet JP, Zald D, Versace R, et al. Emotional responses to pleasant and unpleasant olfactory, visual, and auditory stimuli: a positron emission tomography study. J Neurosci 2000;20:7752–9.
Please cite this article in press as: Desai M et al. Olfactory abnormalities in temporal lobe epilepsy. J Clin Neurosci (2015), http://dx.doi.org/10.1016/ j.jocn.2015.03.035
