Subthalamic deep brain stimulation in Parkinson's disease with SNCA mutations: Based on the follow‐up to 10 years

Abstract Backgrounds Although the short‐term efficacy of bilateral subthalamic deep brain stimulation (DBS) has been reported in a limited number of Parkinson's disease (PD) patients with SNCA mutations, there are no data for long‐term outcome. Methods This multicenter retrospective study investigated previously reported PD patients with SNCA mutations, implanted with bilateral subthalamic DBS. We compared demographic and clinical data at baseline and last follow‐up. Clinical data of motor and nonmotor symptoms and motor fluctuation were collected up to 10 years from DBS surgery. Results Among four subjects, three had SNCA duplication and one had c.158C.A (p.A53E) mutation. The mean post‐implantation follow‐up duration was 5.4 ± 3.7 years. All patients with SNCA duplication showed favorable outcome, although one died from breast cancer 1.5 years after DBS. The patient with the missense mutation became wheelchair‐bound due to progressed axial, cognitive and psychiatric symptoms after 3.5 years from DBS despite the benefit on motor fluctuation. Conclusion Based on findings in our small cohort, subthalamic DBS could be beneficial for motor fluctuation in PD patients with SNCA mutations, especially those with SNCA duplication, and cognitive and psychiatric symptoms are important for the long‐term outcome of subthalamic DBS.

, long-term outcome of STN DBS is important when we take DBS into account as a possible treatment option in PD patients from SNCA mutations. Therefore, we investigated long-term outcome of bilateral STN DBS in PD patients with SNCA mutation (missense mutations and multiplications) by a worldwide multicenter retrospective and cross-sectional study.

METHODS
This study was approved by the Institutional Review Board of Samsung Medical Center and involved hospitals. Although this study is not a systemic review, we used the previous guideline for a systemic review to find reported STN DBS cases with SNCA mutations (Page et al., 2021), and then we collected the long-term outcome by contacting the authors of each reported case. Literature searches were conducted in PubMed search from inception on 1 February 2019 with keywords "SNCA or α-synuclein gene" and "deep brain stimulation or DBS." The initial search identified 31 articles with English language. Exclusion cri-  (Antonini et al., 2012;Martikainen et al., 2015;Shimo et al., 2014). Additionally, we also included 1 PD patient with SNCA duplication with bilateral STN DBS at Samsung Medical Center, Seoul, Korea.
All the data at the baseline (pre-DBS), and the last follow-up after
No patients demonstrated dementia and mean MMSE score was 29.3 ± 1.0 before DBS. There were no surgical complications, while devicerelated complication was reported in case #4. In case #4, DBS was removed 1 year after surgery because of infection and reimplanted 6 months after removal.

Outcome of bilateral subthalamic DBS
Two subjects with SNCA duplication (case #2 and #3) were followed up to 6.5 and 10 years from DBS and revealed excellent motor outcome from bilateral STN DBS (Table 1). Nonmotor symptoms were also stable in these subjects. Another patient with SNCA duplication (case #1) died from breast cancer 1.5 years after DBS, but her parkinsonism was wellcontrolled till her death.
In the subject with missense mutation (case #4), disease itself progressed with levodopa-nonresponsive or -induced symptoms such as depression, perceptional problem, and cognitive decline. However, motor benefit from STN DBS was still evident, considering she still took PD medications less frequently with less dyskinesia compared to the baseline.

DISCUSSION
This is the first study to investigate the outcome of STN DBS up to 10 years in the PD patients with SNCA mutations. Despite small number of patients, our results suggest a good outcome in the three cases with duplications whereas outcome in the patient with the missense mutation was not robust because of axial symptoms and cognitive and psychiatric problems.   Duration was scored based on UPDRS part 4 item #32 and #39: 0: none, 1: 1%-25% of day, 2: 26%-50% of day, 3: 51%-75% of day, 4: 75%-100% of day.
relatively stable cognition and hallucination during entire follow-up up to 10 years from DBS, and anxiety even improved in one of two subjects (case #3). On the other hands, cognitive and psychiatric symptoms were deteriorated as well as axial motor symptoms in a patient (case #4) who showed unfavorable outcome from STN DBS.
In spite of motor benefit from STN DBS, the different outcomes in cognitive function among monogenic PDs were already reported (Artusi et al., 2019). Similarly, based on the different outcome between the PD patients with SNCA duplication and missense mutation, genotype could affect the outcome of STN DBS. Among SNCA missense mutation, duplication, and triplication, SNCA triplications had the earliest onset, and duplications had the latest onset. Considering PD with SNCA triplication shows much more aggressive disease progression involving both motor and nonmotor symptoms including cognitive and psychiatric symptoms, DBS itself may not be considered in the patients with SNCA triplication and this can be the reason why there is no case report with DBS case with SNCA triplication. On the other hand, SNCA duplication could present with relatively slow progressive PD compared to triplication or missense mutation. SNCA duplication was also detected in sporadic PD patients (Ahn et al., 2008), and the phenotype may resemble idiopathic PD, including late age-of-onset, slow progression, and less dementia (Chartier-Harlin et al., 2004). Therefore, these could be the reasons why DBS was mostly performed in PD patients with SNCA duplication (Antonini et al., 2012;Perandones et al., 2015;Shimo et al., 2014). However, the progression could be rapid even in PD with SNCA duplication. Indeed, the mother of case #1 revealed rapid progression, and showed full dementia 7 years after disease onset (Antonini et al., 2012). Therefore, even in PD patients with SNCA duplication, it is important to choose those with stable cognitive and psychiatric symptoms as candidate for STN DBS.
Another issue is about the target for DBS in PD patients with SNCA mutation. There is only one report with pallidal stimulation (Perandones et al., 2015). Considering SNCA mutation is associated with psychiatric symptoms or cognitive decline (Book et al., 2018;Wittke et al., 2018), pallidal stimulation could be safer option than subthalamic stimulation. However, PD patients with SNCA mutation are relatively young, thus there is more need to reduce PD medication. Moreover, the reduction of medication dose is also important to improve perceptional problem. In our study, hallucination was seen in three of four subjects (case #2-4) but deteriorated only in one subject with missense mutation (case #4) after DBS. Additionally, even with STN DBS, many studies reported preserved or improved cognition or psychiatric symptoms (Boel et al., 2016). Therefore, we suggest STN could be preferred target than globus pallidus interna if the candidates with SCNA mutations had stable cognitive and psychiatric symptoms.
Our study has some limitations. Our results were based on small number of cases, and it is difficult to generalize to all PD patients with SNCA mutation or even to all patients with SNCA duplication. Additionally, we recruited PD patients with SNCA mutation, who already had performed bilateral STN DBS. This may result in a selection bias that rapidly progressive patients with SNCA mutation should not be even considered as a candidate for DBS. Lastly, this is a retrospective study, thus we could not use unified protocol for evaluation of efficacy.
However, we tried our best to illustrate all the scales and evaluations as possible.
In conclusion, based on findings in our small cohort, STN DBS is beneficial for motor fluctuation, especially those with SNCA duplication, and cognitive and psychiatric symptoms were important factors for the outcome in PD patients with SNCA mutations.