Reply to: Glioblastoma, <scp>IDH</scp>‐Wildtype, <scp>CNS WHO</scp> Grade 4, Associated with Deep Brain Stimulation in a Patient with Essential Tremor: Report of a Case with Molecular Characterization and Review of the Literature

We read with interest the letter from Burns et al1 regarding a case of glioblastoma associated with deep brain stimulation (DBS) in a patient with essential tremor. Their case adds another example of a high-grade brain tumor in close proximity to DBS electrodes. The nature of the association between DBS and malignancy remains unknown. The generally accepted incidence of high-grade glioma (HGG) is ~3.56/100,0002 in the United States. With more than 280,000 patients implanted with DBS worldwide,3 we could expect perhaps 10 DBS patients per year to be affected. To date, seven cases have been catalogued in the literature from 2010 to 2022,1 however, there may be more unreported cases. It remains unclear whether the rate of HGG is higher in patients with DBS. Thus far very few cases have been reported. A caveat is that most DBS are implanted for Parkinson's disease (PD),3 and if factors such as longer implantation and stimulation times were to increase the risk of HGG, then perhaps it takes many years longer than most PD patients live post-DBS to see malignancy develop. Hence, the observed incidence might not represent true risk in relation to DBS. The risk in subpopulations of DBS patients with longer duration implantation for dystonia, epilepsy, or neuropsychiatric indications may be higher. In our case, we highlight HGG in longer-term exposure of more than 20-years of DBS in a DYT-1 dystonia patient implanted at a younger age.4 Furthermore, the tumor centered in the cerebral peduncle, which is an uncommon location for spontaneous HGG. Although any associations remain theoretical, DBS is known to increase the expression of trophic factors and drive neurogenesis.5 With this in mind, DBS driving neoplasia would not be entirely surprising. Further studies will be needed to assess for a causal relationship such as by cataloguing tumor genotypes to understand if certain profiles are present in DBS-associated malignancy, as done by Burns et al.1 Additionally, understanding tumor location relative to the volume of tissue activated and not just the electrode location would be important in future studies. Even if DBS is implicated in increasing neoplasia, the risk is likely low given the low incidence seen to date. If the benefit of DBS therapy such as in refractory dystonia or tremor outweighs the low risks, then many clinicians and patients would likely still elect for DBS except in known cases of higher risk for brain malignancy, similar to other treatments like radiation therapy with risk of secondary malignancy decades later. In conclusion, the case presented by Burns et al1 is another important addition to the literature highlighting HGG in the context of DBS, and further highlights the need for more documentation of such cases and future studies investigating any association of DBS and chronic stimulation with brain malignancy. (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique. A.Balanchandar: 1C, 2A, 2B, 3A. A.Boutet: 1C, 2A, 2B, 3A, 3B. A.V.: 1C, 2C, 3B. J.G.: 1C, 2B. I.Y.M.C.: 1A, 2C, 3B. D.M.: 1A, 2C, 3B. R.P.M.: 1A, 2C, 3B. A.F.: 1A, 2C, 3B. S.K.K.: 1A, 1B, 2C, 3B. A.M.L.: 1A, 1B, 2C, 3B. Ethical Compliance Statement: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. The authors confirm that the approval of an institutional review board was not required for this work. Informed consent was obtained for this case report. Funding Sources and Conflicts of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work. Financial Disclosures for the Previous 12 Months: A.Balachandar, A.Boutet, A.V., J.G., I.Y.M.C., D.M., and R.P.M. report no funding sources in the past 12 months. A.M.L. and A.F. received honoraria and/or research support from Abbott, Insightec, Boston Scientific, and Medtronic. S.K.K. received grants/grants pending from the Canadian Institutes of Health Research, and received payment for lectures including service on speaker's bureaus from Medtronic.

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