Deep brain stimulation and stereotactic-assisted brain graft injection targeting fronto-striatal circuits for Huntington’s disease: an update

ABSTRACT

Introduction

Huntington’s Disease as progressive neurological disorders associated with motor, behavioral, and cognitive impairment poses a therapeutic challenge in case of limited responsiveness to established therapeutics. Pallidal deep brain stimulation and neurorestorative strategies (brain grafts) scoping to modulate fronto-striatal circuits have gained increased recognition for the treatment of refractory Huntington’s disease (HD).

Areas covered

A review (2000–2022) was performed in PubMed, Embase, and Cochrane Library covering clinical trials conceptualized to determine the efficacy and safety of invasive, stereotactic-guided deep-brain stimulation and intracranial brain-graft injection targeting the globus pallidus and adjunct structures (striatum).

Expert opinion

Stereotactic brain-grafting strategies were performed in few HD patients with inconsistent findings and mild-to-moderate clinical responsiveness with a recently published large, randomized-controlled trial (NCT 00190450) yielding negative results. We identified 19 in-human DBS trials (uncontrolled) targeting the globus pallidus internus/externus along with randomized-controlled trial pending report (NCT 02535884). We did not detect any significant changes in the UHDRS total score after restorative injections, while in contrast, the use of deep-brain stimulation resulted in a significant reduction of chorea. GPi-DBS should be considered in cases where selective chorea is present. However, both invasive therapies remain experimental and are not ready for the implementation in clinical use.

KEYWORDS:

• Huntington´s disease
• fronto-striatal circuits
• chorea
• parkinsonism
• dystonia
• globus pallidus externus/internus
• deep-brain stimulation
• striatum
• brain grafts
• unified Huntington´s disease rating scale (UHDRS)
• chorea
• safety
• efficacy
• quality of life

Article highlights

• GPi DBS prompted a meaningful improvement of HD chorea in several uncontrolled trials despite earlier reports of lesioning pallidotomy awaiting results from an ongoing controlled trial

• Reliable, predictive biomarkers (neuroimaging, electrophysiology) are not available for DBS in HD

• Neurorestorative therapies like intracranial fetal cells (graft) injection failed to meet endpoints in a most recent controlled study

• Currently DBS as well as stereotactic brain graft injections remain experimental

Author contributions

Conceptualization: Thomas Kinfe, Martin Nüssel, Yining Zhao, Andreas Stadlbauer, Michael Buchfelder, and Alessandro Del Vecchio. Methodology: Thomas Kinfe. Investigation: Thomas Kinfe, Martin Nüssel, Yining Zhao, Andreas Stadlbauer, Michael Buchfelder. And Alessandro Del Vecchio. Resources: Thomas Kinfe Martin Nüssel. Writing—original draft preparation: Thomas Kinfe, Yining Zhao, Andreas Stadlbauer, Michael Buchfelder and Alessandro Del Vecchio. Writing—review and editing: Thomas Kinfe. Supervision: Thomas Kinfe.

All the authors have read and agreed to the published version of the manuscript.

Declaration of Interest

TM Kinfe has received consultant payments from Medtronic Inc. and Abbott Inc., and has congress travel support and speaker’s fees from Abbott Inc. Yining Zhao received a grant (fellowship) from Abbott Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Institutional review board statement

‘Not applicable.’ for studies not involving humans or animals. You might also choose to exclude this statement if the study did not involve humans or animals.

Reviewer disclosure

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.