Treatment response within the phase I EDEN trial of dentate nucleus DBS for higher extremity hemiparesis from stroke was encouraging, enabling the process to advance to a phase II randomized managed trial to judge security and efficacy.
“We hypothesized that stimulating the dentatothalamocortical pathway, which connects the cerebellum and the cortex, would facilitate the spared perilesional cortex following ischemic stroke,” says Dr. Machado, Chair of Cleveland Clinic’s Neurological Institute. “We further proposed that this stimulation, when paired with physical training, would promote greater functional restoration than could be achieved with physical training alone. That is what we observed in this phase I study, as patients with even minimal residual distal function responded well.”
The findings construct on greater than a decade of preclinical work led by Dr. Machado and Dr. Baker (Neurosurgery. 2013;73:344-353) exhibiting that DBS of the dentate nucleus enhanced perilesional excitability together with perilesional motor cortical reorganization and synaptogenesis. “These results show that the effects seen in our preclinical models appear to translate to humans. They argue for further investigation in larger patient samples.”
The EDEN trial (Electrical Stimulation of the Dentate Nucleus for Upper Extremity Hemiparesis Due to Ischemic Stroke) (NCT02835443) was a single-arm, open-label examine performed at Cleveland Clinic. It enrolled 12 sufferers with continual, average to extreme hemiparesis of the higher extremity following unilateral center cerebral artery stroke 12 to 36 months beforehand.
All sufferers started supervised bodily rehabilitation i.e., bodily and occupational remedy previous to implantation of a DBS lead on the dentate nucleus contralateral to their stroke lesion. After implantation, sufferers underwent bodily rehabilitation for 2 months adopted by a month of DBS programming over a number of classes.
“All patients had three months of structured rehabilitation before the stimulation was turned on, to maximize the benefit to be achieved from rehabilitation alone,” Dr. Machado explains.
This was adopted by a minimum of 4 months of mixed rehabilitation remedy and DBS. The examine’s adaptive design allowed for extension past 4 months if sufferers continued to indicate month-over-month enchancment.
Treatment response was outlined as an enchancment of 4.5 factors or extra on the Fugl-Meyer evaluation of higher extremity perform (FMA-UE). Additionally, the investigators evaluated event-related EEG and native area potentials perioperatively.
All 12 sufferers accomplished the examine. There had been no deaths, hemorrhages, infections or different main perioperative issues. The first three sufferers skilled DBS-related nausea within the first postoperative days. “This appeared to be related to how we placed the electrodes, so we changed that and subsequent patients had no nausea,” Dr. Machado notes.
Treatment response (≥ 4.5-point enchancment on the FMA-UE) was achieved by 9 of 12 sufferers. Mean FMA-UE enchancment was 11.8 factors (± 7.1 SD). Among the seven sufferers who entered the examine with a minimum of minimal distal motor perform, the imply enchancment was 16.4 factors (± 3.9 SD) and was related to important enchancment in actions of each day residing (ADLs).
“This suggests that patients who have a bit of the neuronal pathway preserved offer us more to work with,” Dr. Machado stated. “There appear to be some neurons surviving that the stimulation and physical training can activate and boost.”
Follow-up continued for as much as eight months for some sufferers, with the intention to seize cumulative useful enchancment previous to plateauing. Additionally, perioperative stimulation of the dentate nucleus mixed with EEG revealed that DBS was related to topography- and frequency-specific modulation of movement-related cortical exercise, the investigators reported.
They had been additionally in a position to examine the exercise of the dentate nucleus throughout motion and motion planning. “This is the first reported direct investigation of movement-related local field potentials in the human dentate nucleus,” Dr. Machado notes.
The quality-of-life implications for examine individuals who responded to remedy have been important. At the CNS assembly, Dr. Machado shared a video of a affected person throwing a ball together with her affected hand. “Prior to DBS and physical training, this patient was unable to unclench her hand and release a ball,” he explains. “Now she can coordinate all the movements needed to throw extending and opening the fingers, extending the wrist and so forth and execute them in an organized fashion.”
This capacity has translated to ADL enhancements for this affected person corresponding to the power to place dishes away and have a tendency to numerous family duties. Additional examples embrace a affected person who has regained the power to put in writing messages utilizing a marker and one other who can buckle his pants once more, enabling him to independently go to restrooms in public.
The diploma of imply FMA-UE enchancment achieved within the examine practically triple the clinically significant threshold of 4.5 factors shocked the investigators. “We were not expecting this magnitude of functional recovery in phase I testing,” Dr. Machado says.
In the wake of those findings, Cleveland Clinic is planning a randomized, sham-controlled examine of dentate nucleus DBS in as much as 40 post-stroke sufferers. Dr. Machado says recruitment will probably be restricted to sufferers with a minimum of modest residual distal higher extremity perform, in view of the superior response on this affected person subgroup.
He provides that the following examine will even incorporate refinements in implantation methods adopted over the course of the phase I examine.
“About half of chronic stroke patients have a residual neurological deficit severe enough to require assistance with ADLs, even after extensive rehabilitative training,” Dr. Machado concludes. “We clearly need a tool that enhances the effects of physical training. DBS of the dentate nucleus shows encouraging promise to be such a tool. We are eager to investigate it further.”
The examine was supported by the National Institutes of Health’s BRAIN initiative and funding from Enspire DBS Therapy.