Bilateral deep brain stimulation of the fornix for Alzheimer's disease: surgical safety in the ADvance trial

Abstract

OBJECT This report describes the stereotactic technique, hospitalization, and 90-day perioperative safety of bilateral deep brain stimulation (DBS) of the fornix in patients who underwent DBS for the treatment of mild, probable Alzheimer's disease (AD). METHODS The ADvance Trial is a multicenter, 12-month, double-blind, randomized, controlled feasibility study being conducted to evaluate the safety, efficacy, and tolerability of DBS of the fornix in patients with mild, probable AD. Intraoperative and perioperative data were collected prospectively. All patients underwent postoperative MRI. Stereotactic analyses were performed in a blinded fashion by a single surgeon. Adverse events (AEs) were reported to an independent clinical events committee and adjudicated to determine the relationship between the AE and the study procedure. RESULTS Between June 6, 2012, and April 28, 2014, a total of 42 patients with mild, probable AD were treated with bilateral fornix DBS (mean age 68.2 ± 7.8 years; range 48.0-79.7 years; 23 men and 19 women). The mean planned target coordinates were x = 5.2 ± 1.0 mm (range 3.0-7.9 mm), y = 9.6 ± 0.9 mm (range 8.0-11.6 mm), z = -7.5 ± 1.2 mm (range -5.4 to -10.0 mm), and the mean postoperative stereotactic radial error on MRI was 1.5 ± 1.0 mm (range 0.2-4.0 mm). The mean length of hospitalization was 1.4 ± 0.8 days. Twenty-six (61.9%) patients experienced 64 AEs related to the study procedure, of which 7 were serious AEs experienced by 5 patients (11.9%). Four (9.5%) patients required return to surgery: 2 patients for explantation due to infection, 1 patient for lead repositioning, and 1 patient for chronic subdural hematoma. No patients experienced neurological deficits as a result of the study, and no deaths were reported. CONCLUSIONS Accurate targeting of DBS to the fornix without direct injury to it is feasible across surgeons and treatment centers. At 90 days after surgery, bilateral fornix DBS was well tolerated by patients with mild, probable AD. Clinical trial registration no.: NCT01608061 ( clinicaltrials.gov ).

Keywords: AD = Alzheimer's disease; ADAS-cog-11 = Alzheimer's Disease Assessment Scale cognitive subscale; AE = adverse event; Alzheimer's disease; DBS = deep brain stimulation; DBS-f = deep brain stimulation of the fornix; IPG = internal pulse generator; PD = Parkinson's disease; SAE = serious adverse event; deep brain stimulation; dementia; fornix; functional neurosurgery; memory.

FIG. 1

Stereotactic accuracy. A: The angles encountered for the descending columns of the fornix (the solid line indicates the mean angle, 65.7°; the dashed line indicates the standard deviation, ± 7.5°; the dotted line indicates the range, 52.2–79.6°). B: Calculation of the radial (r) and vector (v) errors. The intended trajectory (dotted line) and target (circle) are shown, with the distance from the distal-most contact to the intended target measured. C: To-scale drawing showing the mean radial and vector errors to the distal-most contact of the Medtronic 3387 (Medtronic, Inc.) DBS lead. The bands indicate the 4 contacts on the lead. Used with permission from Barrow Neurological Institute, Phoenix, Arizona.

FIG. 2

Example of the stereotactic plan for targeting the fornix. The trajectory (dotted line) passes approximately 2 mm anterior to the anterior border of the fornix. A = anterior; DBS = deep brain stimulation; deg = degrees; I = inferior; P = posterior; S = superior.

FIG. 3

Chronological occurrence of adjudicated AEs in the ADvance Trial. Black indicates serious AEs.

FIG. 4

Number of patients experiencing multiple AEs. Black indicates serious AEs.

FIG. 5

Classification and number of AEs.Black indicates serious AEs.

FIG. 6

Rates of occurrence of specific AEs. Black indicates serious adverse events. GI = gastrointestinal; GU = genitourinary.