SEARCH

SEARCH BY CITATION

Keywords:

  • deep brain stimulation;
  • odor identification;
  • Parkinson's disease

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of conflicts of interest
  9. References

Background and purpose

Olfactory dysfunction is common in Parkinson's disease (PD) and it is one of the earliest non-motor symptoms. A few studies have suggested that deep brain stimulation of the subthalamic nucleus (STN-DBS) could improve olfactory function. Our aim was to evaluate the acute effect of bilateral STN-DBS on a commonly used smell test in PD patients.

Methods

Fifteen PD patients who underwent bilateral STN-DBS and 15 controls were recruited. Patients and controls were tested for odor identification.

Results

No statistical differences were documented between ON and OFF STN-DBS acute stimulation concerning olfaction. Controls presented a better performance for olfactory identification than patients.

Conclusions

Our exploratory study did not support that bilateral STN-DBS could have an acute effect on olfactory function in PD patients.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of conflicts of interest
  9. References

Olfactory dysfunction is a frequent and early non-motor symptom (NMS) of Parkinson's disease (PD) [1]. Olfactory loss in idiopathic PD is bilateral and unrelated to disease stage, antiparkinsonian medication or motor fluctuations [2]. Deficits in olfactory function (OF) in PD are described in each of the three olfactory domains: odor identification (OI), odor discrimination and detection threshold.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an established treatment for levodopa-induced motor complications in PD and improvement of NMS with STN-DBS has also been reported [3]. The effect of DBS on OF is controversial with very few reports investigating it [4, 5]. This study aimed to evaluate the acute effect of bilateral STN-DBS on OI in 15 PD patients.

Subjects and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of conflicts of interest
  9. References

Subjects

Fifteen PD patients fulfilling a diagnosis of idiopathic PD according to the UK Brain Bank [6], who underwent bilateral STN-DBS, were consecutively recruited from the movement disorders outpatient clinic of the Hospital Santa Maria, Lisbon, Portugal. The Institutional Review Board approved the study and all patients provided informed consent to participate and for the publication of individual clinical details. Patients were excluded if they scored ≤24 in the Mini-Mental State Examination (MMSE) at the time of olfaction assessment. During the evaluation stimulation patterns were as follows: stimulation frequency (130 Hz), stimulation pulse width (60 μs) and stimulation voltage (0.8–3.4 V). After surgery the mean reduction of levodopa equivalent daily dose was of 770 mg (64% of the pre-surgery dose). Fifteen healthy volunteers with neither cognitive impairment (MMSE ≤ 24) nor PD signs were included as age-, education- and sex-matched controls.

Assessments

Patients and controls were tested for OI using the Sniffin' sticks test (SS-16) [7]. Control subjects were tested once, whereas PD patients were assessed in two conditions, during the same day: after stimulation had been switched off for at least 30 min (stimulation OFF\medication ON) and after stimulation had been switched on for at least 30 min (stimulation ON\medication ON). During each of these sessions, SS-16 and Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III were applied; patients were also interviewed using the MDS-UPDRS parts I and II. Patients were randomized to have the first session with the stimulator ON (group A: ON [RIGHTWARDS ARROW] OFF) or the stimulator OFF (group B: OFF [RIGHTWARDS ARROW] ON) to minimize the effect of familiarization with the test. For convenience, the evaluation on ON stimulation is labeled A1 and the evaluation during OFF stimulation is labeled A2 in session A; equally, B1 is the evaluation on OFF stimulation and B2 on ON stimulation in session B. Patients and rater were aware whether stimulation was ON or OFF. Subjective perception of olfaction deficit was evaluated using the Non-motor Symptoms Assessment Scale for PD (Question 28; score range 0–3).

Statistics

Carry-over and training effects were investigated by comparing the percentage of SS-16 correct answers of A1 with B2, A2 with B1 and B2 + A2 with A1 + B1, respectively, using the Mann–Whitney U test. Frequency of correct answers for the SS-16 was then compared between ON stimulation and OFF stimulation and between controls and patients, using the Mann–Whitney U test. The Wilcoxon signed rank test was used to compare the MDS-UPDRS-III score during ON and OFF stimulation. The frequency of correct answers for the SS-16 between patients who had undergone surgery within the last 6 months and those who had been implanted more than 6 months ago was explored using the Mann–Whitney U test. Finally the subjective perception of olfaction deficit was compared with the correct answer percentage and the MDS-UPDRS-III of patients operated 1 month before was compared with that of patients operated later using the Mann–Whitney U test. Results were analyzed using the software package SPSS 11.0 for Windows (Chicago, IL, USA) and post hoc power was calculated. A P value <0.05 was considered statistically significant.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of conflicts of interest
  9. References

Demographic, clinical and SS-16 data of the patients are detailed in Table 1. Neither carry-over nor training effects were observed (respectively P = 0.619 and P = 0.407). The MDS-UPDRS-III score was significantly different between ON and OFF stimulation (OFF, mean 49.1 ± 15.7; ON, mean 28.1 ± 12; P = 0.001) whilst there was no difference between patients operated 1 month before and those operated earlier (P = 0.471). The performance for SS-16 was significantly different between controls (12 ± 1.8, range 8–15) and patients (= 0.001; Fig. 1), but not for ON stimulation versus OFF stimulation (P = 0.653; Table 1). There was no effect of time elapsed from surgery (≤6 months vs. >6 months; = 0.189) on smell perception and no correlation between subjective perception of olfaction impairment and the objective test results (P = 0.1). The post hoc power was 0.114.

Table 1. Demographic, clinical and OI data of patients
Subject numberGenderAgeEducation (years)Disease duration (years)MMSE (score)Hoehn and Yahr stage (ON)Months after DBSUPDRS IUPDRS IIUPDRS III ONUPDRS III OFFSession orderSS-16 score (OFF)% correct answers OFF% correct answers ONChange from OFF to ON in SS-16 score
1M66411302167233181ON [RIGHTWARDS ARROW] OFF42525=
2M631215292104122338ON  [RIGHTWARDS ARROW] OFF637.531.2[DOWNWARDS ARROW]
3M4513830221092349OFF  [RIGHTWARDS ARROW] ON743.756.2[UPWARDS ARROW]
4M714212834210314163OFF [RIGHTWARDS ARROW] ON531.237.5[UPWARDS ARROW]
5M65517292361101831OFF [RIGHTWARDS ARROW] ON637.537.5=
6M64414302613151840ON [RIGHTWARDS ARROW] OFF85050=
7F62414282112151940ON  [RIGHTWARDS ARROW] OFF85068.7[UPWARDS ARROW]
8F5341629239131830OFF  [RIGHTWARDS ARROW] ON956.268.7[UPWARDS ARROW]
9F654212722610133649ON  [RIGHTWARDS ARROW] OFF743.750[DOWNWARDS ARROW]
10F671627292614213353OFF [RIGHTWARDS ARROW] ON637.543.7[UPWARDS ARROW]
11F743182546320436175OFF [RIGHTWARDS ARROW] ON42512.5[DOWNWARDS ARROW]
12M704143025751640ON [RIGHTWARDS ARROW] OFF531.225[DOWNWARDS ARROW]
13M511214292365162939OFF  [RIGHTWARDS ARROW] ON85068.7[UPWARDS ARROW]
14F5020123021682141ON [RIGHTWARDS ARROW] OFF1593.793.7=
15M624202627820173568OFF  [RIGHTWARDS ARROW] ON531.231.2=
Median 64416292169152341 65037.5 
Interquartile range 148620397111724 33843.5 
image

Figure 1. Mean and SD for correct answer percentage on SS-16 in control subjects and PD patients with ON stimulation and OFF stimulation.

Download figure to PowerPoint

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of conflicts of interest
  9. References

Our exploratory study did not find any difference between ON and OFF STN-DBS acute stimulation effect concerning OI amongst a PD hyposmic population. It should be noted that only one patient (14_F), with early-onset PD and a probable recessive inheritance, had a marked high score on SS-16, but 10% of PD patients could not have hyposmia, particularly some of the monogenic forms. The significant differences in MDS-UPDRS-III score during ON and OFF stimulation confirmed that the tested PD population had a good response to DBS and showed that improvement in motor performance does not parallel a modification in OF.

STN-DBS is known to have an effect on some NMS of PD [3]. However, the DBS impact on OF has only been investigated twice in small groups of 11 and 15 PD patients [4, 5]. These papers report an improvement of odor discrimination during ON stimulation, whilst no changes were noted for detection threshold and OI was not explored. One isolated case report shows dramatic improvement of OI after bilateral STN-DBS [8]. However, in this case the stimulator had been turned off for 7 days before testing suggesting that a longer wash-out might be useful in future studies aiming to demonstrate the effect of DBS on olfaction. Moreover in a previous study using OI in 16 PD patients ON and OFF medication with a wash-out period <24 h showed no difference in OI despite a significant motor improvement [3], and a longitudinal study failed to show consistent worsening with time despite deterioration of motor performance [9].

Neuronal degeneration with deposition of α-synuclein within the olfactory bulb, the anterior olfactory nucleus and the limbic rhinencephalon occurs early in PD [10] and olfactory deficit seems to be related to this neuropathological change. This notion would not predict an improvement with DBS, given that the neuronal loss in the olfactory structures would be deemed irreversible.

Our study has the limitations inherent to exploratory studies. It has a low post hoc power due to the small group of patients, and the results should be confirmed in a larger sample. It was not possible to test OF in our PD patients before DBS implantation, in order to exclude any possible effect of the surgery procedure itself. In addition the potential effects of antiparkinsonian medication on OF was not explored and blinded tests were not conducted.

In conclusion, our exploratory study does not support the hypothesis that STN-DBS has any short-term effect on OF with regard to OI. It may be hypothesized that if STN functional modulation impacts on OI, it could be via a basal ganglia-thalamo-cortical circuit whose effect may not be as rapid or as visible as the motor changes in PD patients.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of conflicts of interest
  9. References

M.F. acknowledges the support of the work by an EFNS fellowship. We thank Dr Ana Noronha and Dr Maria Finisterra for technical support and all the participating subjects for their contribution. Dr Silveira-Moryiama reports personal fees from Reta Lila Weston Trust for Medical Research, grants from Parkinson's UK and Parkinson's Foundation, personal fees from Teva Lundbeck, grants from UCB, Genus, Abbott and FAPESP, and personal fees and non-financial support from UNICAMP, outside the submitted work. Dr Ferreira reports grants and personal fees from GlaxoSmithKline, grants from Grunenthal, grants from Fundação MSD (Portugal), grants and personal fees from TEVA, other from European Huntington Disease Network, personal fees from Merck-Serono, Lundbeck, Novartis, Merz, Ipsen, Solvay, Abbott and BIAL, and grants from Grunenthal, outside the submitted work.

Disclosure of conflicts of interest

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of conflicts of interest
  9. References

The authors declare no financial or other conflicts of interest.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of conflicts of interest
  9. References