Dear Editor,

Deep brain stimulation (DBS) is a well-established treatment for Parkinson’s disease (PD), but the influence of genetics on long-term outcomes is not fully understood [1,2]. Retrospective studies suggest that genetic factors may shape DBS responses. In the EARLYSTIM trial, patients with the SNCA rs356220 variant had better quality of life after subthalamic nucleus (STN) DBS [3]. A 2020 review showed that while DBS may benefit patients with PD linked to SNCA, GBA1, and LRRK2 variants, these forms often progress rapidly with cognitive decline [4]. PRKN mutations have been associated with better motor outcomes, whereas GBA1 and SNCA variants have been linked to worse cognitive outcomes. We reviewed the outcomes of genetically confirmed PD (gPD) patients who underwent DBS at our institute over the past 10 years.

We retrospectively reviewed outcomes from gPD patients who underwent DBS at our center from 2013 to 2023. Patients with PD with pathogenic or likely pathogenic variants in PD-related genes were included. Patients with variants of uncertain significance or <12 months of follow-up were excluded. Data on demographics, DBS indications, surgical targets, levodopa equivalent daily dose (LEDD), and clinical outcomes were collected. Age at onset (AAO) was classified as juvenile (<21 years), early-onset (21–50 years), or late-onset (>50 years) per the International PD and movement disorders society Task Force 2022. Outcomes included the Unified Parkinson’s Disease Rating Scale Part-III (UPDRS-III), dyskinesia, non-motor scales, Mini-Mental Status Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Hoehn and Yahr stage.

Motor outcomes were based on the UPDRS-III score in off-medication-on-stimulation and off-medication/off-stimulation states. Levodopa responsiveness was assessed across time points and categorized as marked (≥50%), satisfactory (30%–50%), or unsatisfactory (<30%). Changes in cognition (MMSE, MoCA) and LEDD were also analyzed. Follow-up data were stratified into four intervals: first follow-up (F1) (2–3 months), second follow-up (F2) (6–9 months), third follow-up (F3) (1–3 years), and final follow-up (FL) (>3 years). This study was ethically approved by the National Institute of Mental Health and Neurosciences Ethics Committee. Quantitative variables are expressed as the mean±standard deviation. Paired t-tests were used. Analyses were conducted using SPSS v23 (IBM Corp.).

We identified 10 patients (males=7, 70.0%) with gPD-related gene variants by exome sequencing who underwent DBS, with a mean AAO of 36.7±7.8 years (range=18 to 50 years). All had early-onset PD. Notably, family history was positive, and consanguinity was exhibited in 2 patients (20%). The mean age of DBS was 46.9±7.7 years (range 40–60 years), which equated to a mean interval of 10.2±7.2 years of symptoms (range 3–23 years). The mean follow-up duration was 28.2±15.7 months. The mean interval to follow-up was F1: 2.4±0.5 months (n=10), F2: 6.9±0.8 months (n=10), F3: 17.7±3.4 months (n=10), and FL: 40.5±10.3 (range 24 to 60 months) (n=8).

All cases exhibited tremors and bradykinesia. Additional presenting features included dystonia (n=2, 20%), freezing of gait (FoG) (n=2, 20%), postural instability (n=2, 20%), and recurrent falls (n=1, 10%). Levodopa responsiveness was notable in all patients (mean improvement in UPDRS-III score=75.9±16.4%). The key indications for DBS were drug-induced disabling dyskinesia (n=9, 90%) and motor fluctuations (n=9, 90%). The mean UPDRS-III motor scores and LEDD before DBS were 47.7±16.2 and 1216.5±331.5 mg, respectively. The spectrum of non-motor symptoms comprised psychiatric symptoms, namely, depression and anxiety, impulse control disorders (ICDs), rapid-eye-movement behavior disorder, and restless legs syndrome. Quality-of-life status, assessed by the PD Questionnaire-39, was 55.4±14.0. The spectrum of gPDs on whole-exome sequencing identified pathogenic (likely) variants in 4 cases of GBA1 and 2 cases each of SNCA, LRRK2, and PRKN (Table 1, Supplement Table 1 in the online-only Data Supplement)

All but one patient underwent bilateral STN-DBS; one received bilateral globus pallidi interna (GPi) DBS. All showed transient early improvement, likely due to the lesioning effect. Immediate postoperative symptoms included off-state dystonia (30%) and dyskinesia (10%). At F1, the mean UPDRS-III score (on-stimulation-off drugs) improved significantly from baseline (20.6±7.2 vs. 47.7±16.2, p<0.001). Common issues were off-dystonia (20%), tremors (10%), and FoG (20%). LEDD decreased significantly to 611.3±257.8 mg (p<0.001). At F2, motor scores improved (21.8±8.1, p<0.001), and LEDD decreased further to 563.0±239.6 mg (p<0.001). At F3, off-dystonia, dysarthria, postural instability, ICDs, and falls persisted in those with preexisting symptoms, but the UPDRS-III score (19.1±4.7) continued to improve (p<0.001). By the FL, no patients had dyskinesia. Although the reduction in LEDD plateaued (F3 vs. FL, p=0.172), it persisted below F1, consistent with the optimal dosing threshold. MMSE scores decreased (28.3±1.5 to 26.7±1.9, p=0.028), whereas the MoCA scores remained stable (27.2±1.9 to 26.5±2.0, p=0.197) (Supplementary Table 1 in the online-only Data Supplement).

Four patients with GBA1 variants (mean AAO 35±2.9 years) showed significant improvement in UPDRS-III score and a reduction in LEDD; long-term data were available for two patients. MMSE scores decreased initially but stabilized, while MoCA scores remained stable. One patient (patient 2) had persistent FoG even at the 2-year follow-up, while another patient (patient 3) developed dysarthria after DBS, which persisted at the 3-year follow-up. The two siblings with SNCA variants demonstrated motor improvements of 62.7% and 51.3%, respectively, along with a reduction in dyskinesia. Both maintained stable cognition at the last follow-up. Genetic testing using in silico copy number variation analysis revealed a homozygous duplication of approximately 450 bp encompassing exon 6 of the SNCA gene. LRRK2-positive patients had variable outcomes. One patient (patient 7) had persistent symptoms that included severe dysarthria and tremors, whereas another (patient 6) had persistent dysphagia. Both had stable cognition, improved UPDRS-III motor scores, and a reduced LEDD at the 3-year long-term follow-up. Among the two PRKN-related cases, patient 1, who underwent GPi-DBS for dystonia, achieved a 58.5% improvement in UPDRS-III motor score. At the 3-year follow-up, he continued to experience persistent lower-limb tremors (left>right), prolonged off periods, and ICDs. These findings are consistent with previous observations that GPi-DBS provides relatively fewer motor benefits, particularly with regard to tremor, compared to STN. Patient 8, treated with STN-DBS, demonstrated a 37.5% improvement in motor scores; however, FoG, postural imbalance, and a tendency to fall persisted, despite preserved cognitive function at 4 years. These residual axial features are typically less responsive to DBS and likely account for the less favorable overall outcome in this patient (Table 1).

This study traces the clinical and pharmacological progression of patients with gPDs who underwent DBS. Despite genetic heterogeneity, most patients demonstrated favorable motor responses and significant reductions in LEDD. Cognitive scores showed a modest decline over time; however, given the study’s retrospective nature, it is challenging to determine whether this was due to disease progression or the effects of DBS itself. No device-related complications were noted, underscoring the safety of the procedure. DBS had a limited effect on symptoms such as FoG, postural instability, and ICDs. Although previous studies reported cognitive decline in GBA1 carriers, our patients maintained stable cognition following an initial decrease in MMSE scores [5,6]. Previous studies have indicated that cognitive decline in patients with GBA1 mutations typically manifests 2–5 years after surgery [7]. Given that the follow-up duration in our cohort was limited to 24–36 months in all our GBA1 patients, the absence of cognitive decline observed here may be attributable to the relatively short follow-up period. Within the SNCA spectrum of genetic PD, duplications have been associated with slower disease progression and a lower risk of cognitive impairment, which may explain the preserved cognition observed in the present study [8]. A recent meta-analysis revealed generally positive short-term outcomes of STN-DBS in patients with PRKN, LRRK2 (excluding R1441G), and GBA1 variants, although nonmotor outcomes remained inconsistent.

This retrospective study is limited by its small, heterogeneous sample size and variable follow-up. While most gPD patients showed sustained benefits from DBS, some had limited or new symptoms, likely due to underlying genetic progression. Given the prognostic value of genetic testing, realistic counseling on DBS outcomes remains crucial when considering surgery in gPD patients.

Supplementary Material

Notes

Ethics Statement

The study received approval from the National Institute of Mental Health and Neurosciences Institute Ethics Committee (NO. NIMH/DO/IEC [BS & NS DIV]2022-23). Patients’ details were anonymized to maintain patient privacy, and informed consent was obtained for the study, dissemination, and publication.

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement

None

Acknowledgments

None

Author contributions

Conceptualization: all authors. Data curation: Debjyoti Dhar, Vikram Venkappayya Holla, Sneha Dayanand Kamath. Formal analysis: Debjyoti Dhar, Vikram Venkappayya Holla, Sneha Dayanand Kamath. Investigation: Debjyoti Dhar, Vikram Venkappayya Holla. Methodology: Sneha Dayanand Kamath, Nitish Kamble, Vikram Venkappayya Holla, Ravi Yadav, Pramod Kumar Pal. Project administration: Dwarakanath Srinivas, Ravi Yadav, Pramod Kumar Pal. Resources: Vikram Venkappayya Holla, Nitish Kamble, Dwarakanath Srinivas, Ravi Yadav, Pramod Kumar Pal. Supervision: Nitish Kamble, Dwarakanath Srinivas, Ravi Yadav, Pramod Kumar Pal. Writing—original draft: Debjyoti Dhar, Vikram Venkappayya Holla. Writing—review & editing: Sneha Dayanand Kamath, Nitish Kamble, Dwarakanath Srinivas, Ravi Yadav, Pramod Kumar Pal.

REFERENCES

• 1. Asimakidou E, Xiromerisiou G, Sidiropoulos C. Motor and non-motor outcomes of deep brain stimulation across the genetic panorama of Parkinson’s disease: a multi-scale meta-analysis. Mov Disord Clin Pract 2024;11:465–477.ArticlePubMedPMC
• 2. de Oliveira LM, Barbosa ER, Aquino CC, Munhoz RP, Fasano A, Cury RG. Deep brain stimulation in patients with mutations in Parkinson’s disease-related genes: a systematic review. Mov Disord Clin Pract 2019;6:359–368.ArticlePubMedPMCPDF
• 3. Krause P, Reimer J, Kaplan J, Borngräber F, Schneider GH, Faust K, et al. Deep brain stimulation in early onset Parkinson’s disease. Front Neurol 2022;13:1041449.ArticlePubMedPMC
• 4. Kuusimäki T, Korpela J, Pekkonen E, Martikainen MH, Antonini A, Kaasinen V. Deep brain stimulation for monogenic Parkinson’s disease: a systematic review. J Neurol 2020;267:883–897.ArticlePubMedPMCPDF
• 5. Lythe V, Athauda D, Foley J, Mencacci NE, Jahanshahi M, Cipolotti L, et al. GBA-associated Parkinson’s disease: progression in a deep brain stimulation cohort. J Parkinsons Dis 2017;7:635–644.ArticlePubMedPDF
• 6. Weill C, Gallant A, Lintsky E, Dienstag A, Israel Z, Arkadir D. Cognitive effects of deep brain stimulation in GBA-related Parkinson disease. Ann Neurol 2022;92:344–345.ArticlePubMed
• 7. Anis S, Goldberg T, Shvueli E, Kozlov Y, Redlich Y, Lavi N, et al. Are LRRK2 p.G2019S or GBA1 variants associated with long-term outcomes of deep brain stimulation for Parkinson’s disease? Parkinsonism Relat Disord 2024;124:106008.ArticlePubMed
• 8. Youn J, Oyama G, Hattori N, Shimo Y, Kuusimäki T, Kaasinen V, et al. Subthalamic deep brain stimulation in Parkinson’s disease with SNCA mutations: based on the follow-up to 10 years. Brain Behav 2022;12:e2503.PubMedPMC

Figure & Data

References

Citations

Citations to this article as recorded by  

Comments on this article