A Case of Successful Pallidal Deep Brain Stimulation in ANO3 Dystonia

We present a case of successful deep brain stimulation (DBS) of the globus pallidus intern (GPi) in a 23-year-old male with an ANO3 mutation. Mutations in the anoctamin-3 gene (ANO3) are associated with autosomal dominant craniocervical dystonia and dystonic tremors, which typically manifest in adulthood, often accompanied by myoclonic jerks.1 Tisch S. et al2 reported five cases with incomplete responses to bilateral GPi-DBS in ANO3-related dystonia, resulting in heterogeneous outcomes.3-5 Our case involves a 23-year-old male who developed generalized dystonia and axial myoclonus. Symptoms first appeared at age 10 with cervical dystonia, spreading to the lower extremities around age 15, resulting in worsening walking difficulties. By age 20, axial dystonia with trunk hyperextension rendered walking impossible without assistance. Conventional medical treatments, including benzodiazepines, dopamine, neuroleptics, and antiepileptic drugs, were ineffective. Genetic analysis revealed a heterozygous missense variation in the ANO3 gene: chr11_26655820_A_G, c.1943A>G, p.N648S. The patient was initially referred in 2018 to a center where GPi-DBS leads were implanted without success over 4 years of follow-up. Due to the lack of improvement, he was subsequently referred to our center for an evaluation and second opinion. We performed a control MRI (T2 TSE) that showed the leads were in the anterior, limbic part of the GPi (Fig. 1). In 2022, we reoperated to remove the initial leads and target the posterior, motor part of the GPi. We implanted new leads under general anesthesia with direct magnetic resonance imaging (MRI)-guided targeting,6 using new burr-holes to achieve an optimal vertical trajectory, and removed the previous ones. Immediate post-operative MRI confirmed the position of each electrode in the motor segment of the GPi (Fig. 1) with no complications. We implanted two electrodes (3389-lead model, Medtronic Inc., MN, USA) with a rechargeable implantable pulse generator in the abdominal area (Medtronic Activa RC). Stimulation began 5 days post-surgery, and his current DBS settings are left GPi: C+ 1-2- 1.5 V 450 μs 130 Hz 2.2 mA and right GPi: C+ E1-2-1.7 V 450 μs 130 Hz 2.7 mA. Before the second operation, the patient had a motor BFMDRS score of 23 of 120 and a functional BFMDRS score of 8 of 30. He needed a rollator to walk and experienced numerous myoclonus jerks in the upper limbs. After multiple medication trials with no significant improvement, the patient was medication-free after DBS placement. At the 18-month follow-up, he reported significant myoclonus control and improved axial dystonia, enabling him to walk without the rollator and run approximately 2.5 km twice a week. His motor BFMDRS score improved to 3 of 120, a remarkable 87% improvement, and his functional BFMDRS score improved to 5 of 30, a 38% improvement (Video 1). The patient's quality of life substantially improved after the surgery. Our results appear more favorable compared with other reported cases. Various factors, including lead placement and stimulation parameters, may explain these differences. In summary, we present a highly effective GPi-DBS case in a patient with generalized dystonia due to an ANO3 mutation, notably improving myoclonus and axial dystonia and significantly enhancing his walking ability. (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Manuscript preparation: A. Writing of the first draft, B. Review and critique. G.P.: 1B, 1C, 2A, 2B. E.C.S.: 1B, 2C. E.S.: 2C. P.C.: 1A, 1B, 2B. The data that support the findings of this study are available from the corresponding author upon reasonable request.