|Year : 2019 | Volume
| Issue : 2 | Page : 65-72
Change in non-motor symptoms after deep brain stimulation of bilateral subthalamic nuclei in patients with Parkinson’s disease
Rukmini M Kandadai1, Archana Bethala2, Deepika Sirineni3, Suryaprabha Turaga1, Shaik A Jabeen1, Meena A Kanikannan1, Rupam Borgohain1
1 Department of Neurology, Nizam’s Institute of Medical Sciences, Hyderabad, Telangana, India
2 Department of Neurology, Osmania Medical College and Hospital, Hyderabad, Telangana, India
3 Department of Neurology, Apollo Hospitals, Hyderabad, Telangana, India
|Date of Web Publication||13-Aug-2019|
Dr. Rukmini M Kandadai
Department of Neurology, Nizam’s Institute of Medical Sciences, Punjagutta, Hyderabad 500082, Telangana
Source of Support: None, Conflict of Interest: None
BACKGROUND: The role of deep brain stimulation (DBS) of bilateral subthalamic nuclei (STN) in motor improvement of patients with Parkinson’s disease (PD) is well proven. But, the effect DBS has, on non-motor symptoms (NMSs), is still debatable. There are few studies, which have attempted to address this issue, though it also has significant effect on the quality of life of patients. PURPOSE: To study the impact of bilateral STN-DBS on NMSs in patients with PD. SUBJECTS AND METHODS: A prospective study was constructed from a center in South India. Thirty-five patients with PD who underwent bilateral STN-DBS were assessed preoperatively and 6 months postoperatively for NMSs with two well-established questionnaires: Non-motor Symptoms Questionnaire (NMS Q) and Non-motor Symptoms Scale (NMSS). The significance of improvement in scores was assessed with McNemar’s test, chi-square test, and paired two sample t-test for correlated samples. P value significance was set at <0.05. RESULTS: NMSs were seen in all patients. The most frequent symptoms preoperatively were insomnia (66%), nocturia (63%), urgency, and constipation (49% each). Statistically significant reduction after STN-DBS in overall NMSs was noted in both NMS Q (by 2.83, P = 0.008) and NMSS (by 17.40, P = 0.0013). Among the various domains, a significant reduction was observed in cardiovascular and sleep domains with improvement in individual questions on mood, insomnia, and light-headedness. Weight gain was more common after STN-DBS. CONCLUSION: Subthalamic nucleus stimulation causes significant improvement in NMSs with significant improvement in cardiovascular and sleep domains.
Keywords: Deep brain stimulation, non-motor symptoms, Parkinson’s disease
|How to cite this article:|
Kandadai RM, Bethala A, Sirineni D, Turaga S, Jabeen SA, Kanikannan MA, Borgohain R. Change in non-motor symptoms after deep brain stimulation of bilateral subthalamic nuclei in patients with Parkinson’s disease. Ann Mov Disord 2019;2:65-72
|How to cite this URL:|
Kandadai RM, Bethala A, Sirineni D, Turaga S, Jabeen SA, Kanikannan MA, Borgohain R. Change in non-motor symptoms after deep brain stimulation of bilateral subthalamic nuclei in patients with Parkinson’s disease. Ann Mov Disord [serial online] 2019 [cited 2019 Aug 21];2:65-72. Available from: http://www.aomd.in/text.asp?2019/2/2/65/264360
| Introduction|| |
The approach to treatment of Parkinson’s disease (PD) has always concentrated on motor symptoms. It is increasingly recognized that non-motor symptoms (NMSs) occur throughout the disease, and herald the onset of the disease much before the manifestation of the motor symptoms. Recent studies have shown that NMS occurs in almost all patients and causes significant impairment in the quality of life.,, In spite of the significant morbidity that NMSs contribute to, they are often underrated in clinics.
The role of bilateral subthalamic nuclei–deep brain stimulation (STN-DBS) in treating motor symptoms is beyond dispute and improves drug-related side effects such as dyskinesias and motor fluctuations, and causes reduction in dopaminergic medication.,, There are few studies on the effect of bilateral STN stimulation on the NMSs in PD.,, The objective of this study was to evaluate the effect of bilateral STN-DBS on NMSs in a cohort of patients with PD from a tertiary care center in India.
| Subjects and Methods|| |
The study was approved by the institutional ethics committee. Patients with PD who underwent bilateral STN-DBS, between 2009 and 2013, were included. These patients were diagnosed to have PD as per United Kingdom parkinson’s disease brain bank criteria and fulfilled the eligibility criteria for DBS as per Core Assessment Program for Surgical Interventional Therapies protocol that includes age range from 18 to 70 years, disease duration more than 5 years, Unified Parkinson’s Disease Rating Scale motor score (UPDRS-III) in off state more than 30 and UPDRS-III score improvement by 30% with levodopa.,, Patients with atypical syndromes, cognitive dysfunction defined as Montreal cognitive assessment (MoCA) less than 24, depression as assessed by Hospital anxiety and depression scale, severe postural instability, previous surgery for PD, surgical contraindications, active alcohol or drug abuse, and pregnancy were excluded from the study.
All patients were operated by a single neurosurgeon with adequate expertise. Lead implantation was performed under stereotactic guidance with a Cosman-Roberts-Wells frame. Lead positioning was confirmed with intraoperative microelectrode recording. Intraoperative test stimulation was performed to assess improvement of parkinsonian signs and to watch for adverse effects of stimulation. Neurostimulator was implanted either on the same day (10 patients) or within 3 days (25 patients). Postoperative magnetic resonance imaging was performed in all patients with 2mm cuts to correctly identify the optimal DBS electrode. Neurostimulator was turned on, before discharge. Stimulation parameters were adjusted at follow-up as per the standardized protocols for optimal results. All patients were on monopolar stimulation with a pulse width of 60 microseconds and 130 Hz frequency, and amplitude was adjusted as required. Pulse width and frequency were not modified from the initial stimulation and amplitude was maintained constant for 4 weeks before assessment. Medication was slowly tapered based on the improvement with stimulator and was maintained constant for 4 months after surgery.
NMSs: The NMSs were evaluated with Non-motor Symptoms Questionnaire (NMS Q) and Non-motor Symptoms Scale (NMSS) at baseline and follow-up after surgery (minimum of 6 months follow-up).,, The scales were used after obtaining permission from the International Parkinson and Movement Disorder Society. The scales were administered to the patients in the medication “on” phase. NMSS scores were further assessed, divided into nine domains: cardiovascular, sleep/fatigue, mood, perceptual problems/hallucinations, attention/memory, gastrointestinal, urinary, sexual function, and miscellaneous.
Levodopa equivalent daily dose: Levodopa equivalent daily dose (LEDD) was calculated before and after surgery for all patients.
Continuous variables were presented in titer of mean and ± SD. Categorical variables were expressed as proportions, and chi-square test was used to study the difference between the two groups. The significance of improvement in scores was assessed with McNemar’s test, chi-square test, and paired two sample t-test for correlated samples. P value significance was set as <0.05.
| Results|| |
Thirty-five patients (27 males, 8 females) who underwent bilateral STN-DBS with a minimum of 6 months follow-up were included in the study. The mean age of patients was 58.05 ± 8.1 years (range, 38–71 years). The mean duration of disease was 8.37 ± 3.04 years before surgery (range, 5–15 years). The mean duration of follow-up was 14.05 ± 6.48 months (range, 6–30 months). The mean decrease in UPDRS motor scores was 21.8 ± 16.8 in medication “off”–stimulation “on” time.
All patients had one or more NMSs preoperatively. Mean total NMS Q score preoperatively was 6.08+4.98, whereas postoperatively, a statistically significant reduction was observed in the mean score reduction by 2.83 (P = 0.008).
The most common presenting symptoms preoperatively were insomnia (66%), nocturia (63%), urgency, and constipation (49% each). The most common symptoms postoperatively were same with decreased frequency: nocturia (43%), insomnia (34%), urgency, and constipation (37% each) [Table 1].
On individual symptoms, sleep disturbances and difficulty in concentration showed statistically significant decrease (P = −0.03) postoperatively. An increase in frequency of weight change (weight gain) was observed after bilateral STN-DBS [Table 1].
On NMSS, all patients had one or more symptoms. The most common domains affected preoperatively were urinary (80%), sleep/fatigue (80%), gastrointestinal (60%) followed by unexplained pains and weight gain (57%), mood (46%), and attention (40%). The most common symptoms postoperatively were same but with decreased frequency: urinary (74%), sleep/fatigue (51%), gastrointestinal (49%), and cognition/mood (25%). A reduction in frequency was observed in all symptoms except weight changes in miscellaneous, which increased by 17%.
Primary analysis of mean scores on NMSS showed a statistically significant mean decrease in total symptoms score by 17.40 (P = 0.0013). Mean scores decreased in all domains but reached statistical significance in cardiovascular and sleep domains after bilateral STN-DBS [Table 2].
Among the questions covered in cardiovascular domain (the presence of syncope and the presence of light-headedness, dizziness, and weakness on standing from sitting or lying position), no significant difference was reported in the frequency of syncope, but a significant decrease in the score was contributed by light-headedness (P = 0.009) after STN-DBS. The sleep domain covers four questions on excessive daytime somnolence, fatigue or tiredness, difficulty initiating sleep or staying asleep, and symptoms of restless leg syndrome. On individual questions, there was a decrease in mean scores in all; however, statistically significant decrease was noted with difficulty in falling asleep or staying asleep (P = 0.018).
Among individual questions pertaining to other domains, a significant decrease in the scores was contributed by loss of interest and difficulty in experiencing pleasure, which are included in the mood/cognition domain. Weight change was similar in both, but weight loss was noted in pre-DBS state, whereas post-DBS patients noted weight gain [Table 2].
LEDD: There was a significant reduction in levodopa dose at 6 months postoperatively [Table 3].
| Discussion|| |
The impact of bilateral STN-DBS on motor symptoms is well established,,, and similarly in our study, we found a significant improvement in the motor symptoms in the medication “off” state at 6 months with reduction in the medication required.
In the last decade, the emphasis on NMSs has grown and few studies have evaluated the effect of bilateral STN-DBS on NMSs.
In a study by Zibetti et al., the assessment of NMS was carried out by UPDRS and two additional questions regarding constipation and urological dysfunction. They found that salivation, swallowing, and sensory complaints were ameliorated to a comparable degree by the medication “on” state, whether preoperatively or postoperatively. They found an improvement postoperatively as the “on” state persisted longer. In another study by Witjas et al., where non-motor fluctuations were assessed with a questionnaire, pain/sensory fluctuations showed the best response to STN-DBS followed by dysautonomic and cognitive fluctuations.
With the formulation of NMS Q, a more uniform comprehensive assessment was possible. Nazzaro et al. showed a reduction of mean score by five points at 1 year after surgery. Similarly in our study, we found a reduction in the mean of the NMS Q score by approximately three points 6 months postoperatively.
On the use of NMSS, which also quantifies the severity of symptoms, we found a reduction in the severity of NMSS by 17.44. This collaborates with the results described by Wolz et al. who found reduction in the severity of NMS after 6 months after bilateral STN-DBS. Other studies, which are of shorter duration (1 and 4 months after surgery) and longer duration of 24 months after STN-DBS, have shown similar improvement in total NMSS, reiterating the positive effect of STN-DBS on NMS.,
The effect of STN-DBS is not uniform on all NMSs. On individual symptoms combining both NMS Q and NMSS, an improvement was observed in sleep disturbances, light-headedness, attention, and mood. When entire domains were assessed, a significant improvement was observed in cardiovascular and sleep domains in our study.
A recent study published that the most common non-motor domains, which improved after STN-DBS in a cohort of European patients with PD were urinary/sexual functions, mood/cognition, sleep fatigue, and miscellaneous domains. Our study has some overlap and is slightly different and may be related to differences in cultural aspects as well as genetic makeup.
Although the improvement in cardiovascular domain is similar to that noted by Dafsari et al., the effect of bilateral STN-DBS by itself on autonomic control of cardiovascular function seems to be debatable. The effect may be secondary to the reduction in dopaminergic medication, which can worsen orthostatic hypotension.
Subjective sleep improvement after bilateral STN stimulations has also been shown by other studies using NMSS., Improvement in nocturnal mobility may be the major contributing factor with some improvement in sleep fragmentation. However, on objective scales, there are conflicting results regarding the impact of bilateral STN on sleep., Mood improvement as detected on NMSS in our study has been demonstrated in other studies., There is class I evidence that depression is not worsened by STN-DBS with definite evidence that anxiety is improved after STN-DBS.,,
Among all NMSs, only weight gain increased after STN-DBS in our study.
This is validated by similar findings in prior studies., Proposed mechanisms include lesser energy expenditure with decreased motor symptoms of rigidity and dyskinesias, as well as increased food intake as a manifestation of impulse control disorders. This is a significant finding as lifestyle and diet modification may be required after surgery to prevent metabolic complications because of weight gain. [Table 4] compares our findings with other studies assessing NMSs.
|Table 4: Comparison of various studies on non-motor symptoms after STN-DBS|
Click here to view
In our study, LEDD reduced significantly after STN-DBS, which is similar to the other studies. This by itself can improve many NMSs such as orthostatic hypotension (levodopa induced), daytime somnolence (by reducing dopamine agonists), psychosis, and cognitive impairment (reduction of anticholinergics). STN-DBS seems to have a multifactorial effect and improves NMSs by reducing “off” period, medications required as well by direct stimulation effects.
This study looks at the effect of STN-DBS on NMSs in a cohort of Indian patients with PD. The main strength of our study is that the NMSs were assessed by two validated questionnaires of NMS Q and NMSS, which have been proven to have significant correlation with quality of life.,, NMS Q with yes/no questions is a screening test and NMSS is better at quantification of severity of NMSs. But there are certain symptoms such as vomiting, incomplete bowel emptying, falling due to postural instability, vivid/frightening dreams, and acting out of dreams, which are not included in NMSS. Thus, combination of NMS Q and NMSS leads to a more inclusive assessment of NMSs.
The main limitation of this study is the small sample size of the study. The NMS assessment scales used in our study are subjective, and symptoms may be either under- or overreported by patients. Some NMSs such as sexual dysfunction may be underreported, especially in our country because of cultural reasons. The correlation of response of NMSs with motor improvement or medication reduction was not attempted as it was beyond the scope of the paper. We did not assess the exact position of DBS electrode in the STN, which can change its effect on NMSs. Future studies may help in identifying the exact location of lead placement for optimal relief to motor and NMSs.
| Conclusion|| |
Bilateral subthalamic DBS causes improvement in NMSs of PD in addition to motor symptoms. Larger study sizes are needed to confirm these findings in future.
We are extremely grateful to the International Parkinson and Movement Disorder Society for granting us permission to use the NMS Q and NMSS for this study.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Sauerbier A, Ray Chaudhuri K Non-motor symptoms: The core of multi-morbid Parkinson’s disease. Br J Hosp Med (Lond) 2014;75:18-24.
Krishnan S, Sarma G, Sarma S, Kishore A Do nonmotor symptoms in Parkinson’s disease differ from normal aging? Mov Disord 2011;26:2110-3.
Ravan A, Ahmad FM, Chabria S, Gadhari M, Sankhla CS Non-motor symptoms in an Indian cohort of Parkinson’s disease patients and correlation of progression of non-motor symptoms with motor worsening. Neurol India 2015;63:166-74.
Pfeiffer RF Non-motor symptoms in Parkinson’s disease. Parkinsonism Relat Disord 2016;22:119-22.
Gallagher DA, Lees AJ, Schrag A What are the most important nonmotor symptoms in patients with Parkinson’s disease and are we missing them? Mov Disord 2010;25:2493-500.
Benabid AL, Chabardes S, Mitrofanis J, Pollak P Deep brain stimulation of the subthalamic nucleus for the treatment of Parkinson’s disease. Lancet Neurol 2009;8:67-81.
Merola A, Zibetti M, Angrisano S, Rizzi L, Ricchi V, Artusi CA, et al
. Parkinson’s disease progression at 30 years: A study of subthalamic deep brain-stimulated patients. Brain 2011;134:2074-84.
Faggiani E, Benazzouz A Deep brain stimulation of the subthalamic nucleus in Parkinson’s disease: From history to the interaction with the monoaminergic systems. Prog Neurobiol 2017;151:139-56.
Rukmini Mridula K, Borgohain R, Jabeen SA, Padmaja G, Bandaru VS, Ankathi P, et al
. Comparison of frequencies of non motor symptoms in Indian Parkinson’s disease patients on medical management versus deep brain stimulation: A case-control study. Iran J Neurol 2015;14:86-93.
Kurtis MM, Rajah T, Delgado LF, Dafsari HS The effect of deep brain stimulation on the non-motor symptoms of Parkinson’s disease: A critical review of the current evidence. NPJ Parkinsons Dis 2017;3:16024.
Dafsari HS, Silverdale M, Strack M, Rizos A, Ashkan K, Mahlstedt P, et al
; EUROPAR and the IPMDS Non Motor PD Study Group. Nonmotor symptoms evolution during 24 months of bilateral subthalamic stimulation in Parkinson’s disease. Mov Disord 2018;33:421-30.
Hughes AJ, Daniel SE, Kilford L, Lees AJ Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: A clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992;55:181-4.
Defer GL, Widner H, Marié RM, Rémy P, Levivier M Core assessment program for surgical interventional therapies in Parkinson’s disease (CAPSIT-PD). Mov Disord 1999;14:572-84.
Fahn S, Elton RL, Members of the UPDRS Development Committee. The Unified Parkinson’s Disease Rating Scale. In: Fahn S, Marsden CD, Calne DB, Goldstein M, editors. Recent Developments in Parkinson’s Disease. Vol. 2. Florham Park, NJ: Macmillan Healthcare Information; 1987. p. 153-63, 293-304.
Dalrymple-Alford JC, MacAskill MR, Nakas CT, Livingston L, Graham C, Crucian GP, et al
. The MoCA: Well-suited screen for cognitive impairment in parkinson disease. Neurology 2010;75:1717-25.
Bjelland I, Dahl AA, Haug TT, Neckelmann D The validity of the hospital anxiety and depression scale. An updated literature review. J Psychosom Res 2002;52:69-77.
Chaudhuri KR, Martinez-Martin P, Schapira AH, Stocchi F, Sethi K, Odin P, et al
. International multicenter pilot study of the first comprehensive self-completed nonmotor symptoms questionnaire for Parkinson’s disease: The NMSQuest study. Mov Disord 2006;21:916-23.
Chaudhuri KR, Martinez-Martin P, Brown RG, Sethi K, Stocchi F, Odin P, et al
. The metric properties of a novel non-motor symptoms scale for Parkinson’s disease: Results from an international pilot study. Mov Disord 2007;22:1901-11.
Chaudhuri KR, Martinez-Martin P Quantitation of non-motor symptoms in Parkinson’s disease. Eur J Neurol 2008;15:2-7.
Zibetti M, Torre E, Cinquepalmi A, Rosso M, Ducati A, Bergamasco B, et al
. Motor and nonmotor symptom follow-up in parkinsonian patients after deep brain stimulation of the subthalamic nucleus. Eur Neurol 2007;58:218-23.
Witjas T, Kaphan E, Régis J, Jouve E, Chérif AA, Péragut JC, et al
. Effects of chronic subthalamic stimulation on nonmotor fluctuations in Parkinson’s disease. Mov Disord 2007;22:1729-34.
Nazzaro JM, Pahwa R, Lyons KE The impact of bilateral subthalamic stimulation on non-motor symptoms of Parkinson’s disease. Parkinsonism Relat Disord 2011;17:606-9.
Wolz M, Hauschild J, Koy J, Fauser M, Klingelhöfer L, Schackert G, et al
. Immediate effects of deep brain stimulation of the subthalamic nucleus on nonmotor symptoms in Parkinson’s disease. Parkinsonism Relat Disord 2012;18:994-7.
Kurcova S, Bardon J, Vastik M, Vecerkova M, Frolova M, Hvizdosova L, et al
. Bilateral subthalamic deep brain stimulation initial impact on nonmotor and motor symptoms in Parkinson’s disease: An open prospective single institution study. Medicine (Baltimore) 2018;97:e9750.
Dafsari HS, Martinez-Martin P, Rizos A, Trost M, Dos Santos Ghilardi MG, Reddy P, et al
; EUROPAR and the International Parkinson and Movement Disorders Society Non-Motor Parkinson’s Disease Study Group. EuroInf 2: Subthalamic stimulation, apomorphine, and levodopa infusion in Parkinson’s disease. Mov Disord 2019;34:353-65.
Amara AW, Walker HC, Joop A, Cutter G, DeWolfe JL, Harding SM, et al
. Effects of subthalamic nucleus deep brain stimulation on objective sleep outcomes in Parkinson’s disease. Mov Disord Clin Pract 2017;4:183-90.
Witt K, Daniels C, Reiff J, Krack P, Volkmann J, Pinsker MO, et al
. Neuropsychological and psychiatric changes after deep brain stimulation for Parkinson’s disease: A randomised, multicentre study. Lancet Neurol 2008;7:605-14.
Balestrino R, Baroncini D, Fichera M, Donofrio CA, Franzin A, Mortini P, et al
. Weight gain after subthalamic nucleus deep brain stimulation in Parkinson’s disease is influenced by dyskinesias’ reduction and electrodes’ position. Neurol Sci 2017;38:2123-9.
Aiello M, Eleopra R, Foroni F, Rinaldo S, Rumiati RI Weight gain after STN-DBS: The role of reward sensitivity and impulsivity. Cortex 2017;92:150-61.
Ortega-Cubero S, Clavero P, Irurzun C, Gonzalez-Redondo R, Guridi J, Obeso JA, et al
. Effect of deep brain stimulation of the subthalamic nucleus on non-motor fluctuations in Parkinson’s disease: Two-years’ follow-up. Parkinsonism Relat Disord 2013;19:543-7.
Dafsari HS, Petry-Schmelzer JN, Ray-Chaudhuri K, Ashkan K, Weis L, Dembek TA, et al
; EUROPAR; IPMDS Non Motor PD Study Group. Non-motor outcomes of subthalamic stimulation in Parkinson’s disease depend on location of active contacts. Brain Stimul 2018;11:904-12.
[Table 1], [Table 2], [Table 3], [Table 4]