Phenotype distinctions in mice deficient in the neuron-specific α3 subunit of Na,K-ATPase: Atp1a3tm1Ling/+and Atp1a3 +/D801Y.

ATP1A3 is a Na,K-ATPase gene expressed specifically in neurons in the brain. Human mutations are dominant and produce an unusually wide spectrum of neurological phenotypes, most notably rapid-onset dystonia- parkinsonism (RDP) and alternating hemiplegia childhood (AHC). Here we compared heterozygotes of two mouse lines, a line with little or no expression (Atp1a3tm1Ling/+) and a knock-in expressing p.Asp801Tyr (D801Y, Atp1a3 +/D801Y). Both mouse lines had normal lifespans, but Atp1a3 +/D801Y had mild perinatal mortality contrasting with D801N mice (Atp1a3 +/D801N), which had high mortality. The phenotypes of Atp1a3tm1Ling/+ and Atp1a3 +/D801Y were different, and testing of each strain was tailored to its symptom range. Atp1a3tm1Ling/+ mice displayed little at baseline, but repeated ethanol intoxication produced hyperkinetic motor abnormalities not seen in littermate controls. Atp1a3 +/D801Y mice displayed robust phenotypes: hyperactivity, diminished posture consistent with hypotonia, and deficiencies in beam walk and wire hang tests. Symptoms also included qualitative motor abnormalities that are not well-quantified by conventional tests. Paradoxically, Atp1a3 +/D801Y showed sustained better performance than wild type on the accelerating rotarod. Atp1a3 +/D801Y mice were overactive in forced swimming, and afterwards had intense shivering, transient dystonic postures, and delayed recovery. Remarkably, Atp1a3 +/D801Y mice were refractory to ketamine anesthesia, which elicited hyperactivity and dyskinesia even at higher dose. Neither mouse line exhibited fixed dystonia (typical of RDP patients), spontaneous paroxysmal weakness (typical of AHC patients), or seizures, but had consistent, measurable neurological abnormalities. A gradient of variation supports the importance of studying multiple ATP1A3 mutations in animal models to understand the roles of this gene in human disease.Significance statement Different dominant mutations in the neuronal Na,K-ATPase cause an unusually wide range of symptoms in humans. Atp1a3 mouse models also differ greatly in mortality and in visible impairments, but conventional motor tests do not capture their manifestations very well. Two models were compared here with conventional, modified, and novel methods with some surprising results.

Robotic assisted surgery for the treatment of spinal metastases: A case series.

OBJECTIVE: Spinal metastases can significantly affect quality of life in patients with cancer and present complex neurosurgical challenges for surgeons. Surgery with instrumentation is often indicated to alleviate pain, preserve neurological function, and ensure mechanical stability. However, distortions in the bony anatomy due to oncological disease can decrease the accuracy of pedicle screw placement. Robotic-assisted surgery may offer an opportunity to increase screw accuracy and improve navigation of spinal lesions compared to conventional techniques. Therefore, we presented our institutional experience evaluating robotic-assisted surgical fixation for spinal metastases. METHODS: Patients undergoing robotic-assisted surgery at a large tertiary care center between January 2019 - January 2023 for the treatment of spinal metastases were identified. Patient characteristics, including demographics, tumor pathology, surgical complications, and post-operative outcomes were extracted. The Gertzbein Robbins classification system (GRS) was used to assess pedicle screw placement accuracy in patients with post-operative computed tomography. RESULTS: Twenty patients were identified, including 7 females (35 %), with an overall median age of 66 years (range: 39-80 years) and median BMI of 25 kg/m2 (range: 17-34 kg/m2). An average of four spinal levels were instrumented, with metastases located primarily in the thoracic (n=17, 85 %) spine. Common primary tumor types included prostate (n=4), lung (n=2), and plasma cell (n=2) cancers. Most pedicle screws (92 %) were classified as GRS A in patients with postoperative imaging. Post-operative complications were unrelated to the use of the robot, and included pulmonary embolism (n=1), deep vein thrombosis (n=2), and gastric symptoms (n=3). Three patients were readmitted at 30 days, with one reoperation due to tumor recurrence. Four patients were deceased within 6 months of surgery. CONCLUSIONS: Despite the inherent high-risk nature of these surgeries, this study underscores the safety and efficacy of robotic-assisted surgery in the management of spinal metastases. Robots can be helpful in ensuring accuracy of pedicle screw placement in patients with metastatic disease.

Stereotactic body radiation therapy for spinal metastases: A new standard of care.

Advancements in systemic therapies for patients with metastatic cancer have improved overall survival and, hence, the number of patients living with spinal metastases. As a result, the need for more versatile and personalized treatments for spinal metastases to optimize long-term pain and local control has become increasingly important. Stereotactic body radiation therapy (SBRT) has been developed to meet this need by providing precise and conformal delivery of ablative high-dose-per-fraction radiation in few fractions while minimizing risk of toxicity. Additionally, advances in minimally invasive surgical techniques have also greatly improved care for patients with epidural disease and/or unstable spines, which may then be combined with SBRT for durable local control. In this review, we highlight the indications and controversies of SBRT along with new surgical techniques for the treatment of spinal metastases.