Universität zu Köln

Oelkers, Sabina Judith (2025). Outcome Predictors for Deep Brain Stimulation in Patients With Childhood-Onset Dystonia: Short- and Long-Term Evaluation of the GEPESTIM Registry. PhD thesis, Universität zu Köln.

PDF Dissertation_ueberarbeitete_Version_2_nach_Revisionsschein_SabinaJudithOelkers_geb.Giesler.pdf - Accepted Version Download (2MB)

Abstract

Background: Diligent patient selection is of key importance for the treatment success with deep brain stimulation (DBS). Previous studies suggest that a shorter duration of dystonia and a young implantation age may improve the prospects of DBS success2,4,6-11. Children with inherited, isolated dystonia without nervous system pathology and fixed contractures seem to respond better to DBS than patients with other forms of dystonia or patients with structural lesions/neurodegeneration detected in pre-surgery cranial magnetic resonance imaging (cMRI) or patients with diagnoses of orthopaedic deformations2,26. However, little data are available beyond these populations. Objectives: We aim to gain a better understanding as to which patients with dystonia will most benefit from DBS. We measure individual outcomes not only by quantifying motor improvement with the help of the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) but also by taking into account the child's physical development and the question whether and to which extent it was possible to reduce medication postoperatively. In the present study, we sought to identify and re-evaluate clinical factors that might predict the initial, medium-term and long-term responses as well as the maintenance of the benefits over time in paediatric patients undergoing DBS due to various aetiologies and subgroups of dystonia. Methods: For the identification and re-evaluation of these clinical factors, we used the steadily growing online database of the multicentre GEPESTIM registry, which is constantly fed with new information on paediatric DBS. Patients were divided into three groups based on the current international dystonia classification proposed by Albanese et al.: group 1 – isolated inherited and idiopathic dystonia, group 2 – combined inherited and idiopathic dystonia, and group 3 – acquired dystonia1. Clinical evaluation was performed preoperatively, and the postoperative clinical results were summarised in 3 follow-up inter-vals: follow-up 1 (short-term), follow-up 2 (medium-term) and follow-up 3 (long-term). A multiple linear regression model was used to evaluate whether preoperatively known criteria of sex, age at onset of dystonia, age at implantation and duration of disease at the time of surgery were related to short-term, medium-term, and long-term outcomes. Results: Eleven DBS centres from Germany and Austria provided data on 89 patients between the ages of three and 18 years who underwent DBS in the years from 1998 to 2020. In our cohort of 53 male and 36 female subjects, 29 patients were classified into group 1, 29 patients into group 2 and 31 patients into group 3. The group of isolated inherited and idiopathic dystonia showed a significant improvement in the mean BFMDRS values compared to preoperative baseline scores in every follow-up until 4 years after surgery, whereas group 2 showed only mild improvement of BFMDRS values after DBS. For the acquired dystonia cohort, a statistically significant improvement could be displayed in follow-up 2, whereas in the other follow-ups only a minor, non-significant improvement of the BFMDRS values could be detected. In total, mean reduction of pharmaceutical substances prescribed for direct treatment of the movement disorder as well as for non-motor symptoms amounted to 1.5 in short-term follow-up and 1.4 in medium-term and long-term follow-up. DBS also has a statistically significant influence on the physical development of the patients, more precisely, on the age- and gender-specific BMI. Furthermore, 15 age at implantation turned out to be a significant independent predictor of percentage improvement in our regression analysis for the group of patients with isolated dystonia in short-term and medium-term follow-ups. Additionally, in group 1, years of life lived with dystonia before the implantation of DBS cor-related negatively with the clinical outcome expressed by the change of the BFMDRS percentage at all follow-ups. Moreover, important predictors of patient response to pallidal DBS are a preoperative cere-bral MRI without any structural abnormalities, such as structural lesions in the basal ganglia, and the absence of orthopaedic deformities before surgery. Discussion: Our results support the use of pallidal DBS in the treatment of isolated inherited and idio-pathic dystonia in childhood. Since outcomes following pallidal DBS in paediatric patients with acquired or combined inherited and idiopathic dystonia are much more variable, within these patient cohorts, it is even more pivotal to know the predictors of good DBS response when individually assessing whether DBS surgery is indicated. Novel findings of this registry-based analysis are that years of life lived with dystonia before implantation and age at implantation do not seem to serve as preoperative factors aimed at predicting a better re-sponse to DBS for the combined inherited and idiopathic dystonia as well as for the acquired dystonia group. As a result, DBS might not be considered early in every patient diagnosed with dystonia since short disease duration before implantation only led to maximised benefits in the group of isolated dys-tonia, and short-term maximised benefits in the group of acquired dystonia. Invasive neuromodulation for dystonia management should be performed before the often progressive clinical course of dystonia has caused consequential health damage, for example fixed contractures or skeletal deformities20. The accuracy of electrode placement is considered a key determinant of clinical improvement following DBS surgery23. By locating reliable 'sweet spots' and using them as implant sites, the efficiency of DBS can be increased, and computer-guided DBS programming might provide optimal stimulation settings27. Even if selection criteria for DBS procedures exist25, it is necessary to act according to the principles of personalised medicine. The indication for DBS needs to be considered individually with weighing up the risk to benefit ratio, and the patient’s safety and comfort should always be given priority in the individual decision on the optimal time for DBS implantation. In the future, the collected data need to be confirmed by an even greater number of patients. Conclusion: DBS can be an efficacious treatment option for medication-refractory childhood-onset dys-tonia. Younger patients with shorter disease duration and late age at onset suffering from isolated in-herited and idiopathic dystonia fare best after pallidal DBS. Based on our results, this thesis does not necessarily hold for the group of combined inherited and idiopathic as well as for the group of acquired dystonia. Hence, good clinical pheno- and genotyping plays an important role in patient selection. Further multicentre studies are essential to determine the medium- and long-term role of pallidal DBS as well as the impact of neurophysiological/network biomarkers and findings from probabilistic 'sweet spot' analysis as predictors of treatment efficacy in the therapy management of dystonia.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Oelkers, Sabina Judith sabinajudith.oelkers@posteo.de UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-786148
Date:	2025
Language:	English
Faculty:	Faculty of Medicine
Divisions:	Faculty of Medicine > Kinder- und Jugendmedizin > Klinik und Poliklinik für Kinder- und Jugendmedizin
Subjects:	Medical sciences Medicine
Uncontrolled Keywords:	Keywords Language Deep brain stimulation dystonia UNSPECIFIED Outcome predictors UNSPECIFIED GEPESTIM UNSPECIFIED
Date of oral exam:	5 May 2025
Referee:	Name Academic Title Koy, Anne Privatdozentin Dr. Rueß, Daniel Privatdozent Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/78614