Maximal Analgesic Effect Attained by the Use of Objective Neurophysiological Measurements With Closed-Loop Spinal Cord Stimulation.

OBJECTIVES: Spinal cord stimulation (SCS) has been challenged by the lack of neurophysiologic data to guide therapy optimization. Current SCS programming by trial-and-error results in suboptimal and variable therapeutic effects. A novel system with a physiologic closed-loop feedback mechanism using evoked-compound action potentials enables the optimization of physiologic neural dose by consistently and accurately activating spinal cord fibers. We aimed to identify neurophysiologic dose metrics and their ranges that resulted in clinically meaningful treatment responses. MATERIALS AND METHODS: Subjects from 3 clinical studies (n = 180) with baseline back and leg pain ≥60 mm visual analog scale and physical function in the severe to crippled category were included. Maximal analgesic effect (MAE) was operationally defined as the greatest percent reduction in pain intensity or as the greatest cumulative responder score (minimal clinically important differences [MCIDs]) obtained within the first 3 months of SCS implant. The physiologic metrics that produced the MAE were analyzed. RESULTS: We showed that a neural dose regimen with a high neural dose accuracy of 2.8µV and dose ratio of 1.4 resulted in a profound clinical benefit to chronic pain patients (MAE of 79 ± 1% for pain reduction and 12.5 ± 0.4 MCIDs). No differences were observed for MAE or neurophysiological dose metrics between the trial phase and post-implant MAE visit. CONCLUSION: For the first time, an evidence-based neural dose regimen is available for a neurostimulation intervention as a starting point to enable optimization of clinical benefit, monitoring of adherence, and management of the therapy.

The ion channel TRPM7 regulates zinc-depletion-induced MDMX degradation.

Zinc deficiency has been linked to human diseases, including cancer. MDMX, a crucial zinc-containing negative regulator of p53, has been found to be amplified or overexpressed in various cancers and implicated in the cancer initiation and progression. We report here that zinc depletion by the ion chelator TPEN or Chelex resin results in MDMX protein degradation in a ubiquitination-independent and 20S proteasome-dependent manner. Restoration of zinc led to recovery of cellular levels of MDMX. Further, TPEN treatment inhibits growth of the MCF-7 breast cancer cell line, which is partially rescued by overexpression of MDMX. Moreover, in a mass-spectrometry-based proteomics analysis, we identified TRPM7, a zinc-permeable ion channel, as a novel MDMX-interacting protein. TRPM7 stabilizes and induces the appearance of faster migrating species of MDMX on SDS-PAGE. Depletion of TRPM7 attenuates, while TRPM7 overexpression facilitates, the recovery of MDMX levels upon adding back zinc to TPEN-treated cells. Importantly, we found that TRPM7 inhibition, like TPEN treatment, decreases breast cancer cell MCF-7 proliferation and migration. The inhibitory effect on cell migration upon TRPM7 inhibition is also partially rescued by overexpression of MDMX. Together, our data indicate that TRPM7 regulates cellular levels of MDMX in part by modulating the intracellular Zn2+ concentration to promote tumorigenesis.

Refractory CRPS pain treated with psilocybin: A case report.

Psilocybin shows promise as a treatment for CRPS, offering significant pain relief and functional improvement in a patient with refractory symptoms. This case highlights the need for further research into psilocybin's efficacy and optimal dosing for chronic pain management.

Long-COVID symptoms improved after MDMA and psilocybin therapy: A case report.

Key Clinical Message: Long-COVID syndrome lacks effective holistic treatment options. We present a case of a 41-year-old fully vaccinated female with Long-COVID syndrome who obtained significant symptomatic relief after self-medicating with psilocybin and MDMA. Abstract: Long-COVID, a syndrome persisting after the acute phase of coronavirus disease 2019 (COVID-19), lacks effective holistic treatment options. We present a case of a 41-year-old fully vaccinated female with Long-COVID syndrome who obtained significant symptomatic relief by self-prescribing psilocybin and MDMA. Future research is needed to assess safety and efficacy.

Peripheral nerve stimulation (PNS) of the phrenic nerve for intractable hiccups: a novel use case report.

BACKGROUND: Intractable hiccups, defined as those persisting for over 1 month, represent a rare but significant clinical challenge often associated with substantial morbidity and refractory to standard treatments. CASE PRESENTATION: This case report describes the innovative use of phrenic nerve peripheral neuromodulation for managing chronic intractable hiccups in a 73-year-old male patient with a 6-year history of daily hiccups. Conventional treatments and interventional procedures had failed to provide lasting relief. Bilateral phrenic nerve peripheral nerve stimulation (PNS) placed under ultrasound guidance resulted in immediate and substantial improvement, with the patient's Hiccup Assessment Instrument score decreasing from 6/10 to 2/10. The patient experienced significant enhancements in speech and quality of life without complications. CONCLUSIONS: This novel application of phrenic nerve PNS highlights its potential as a therapeutic strategy for intractable hiccups, underscoring their pathophysiologic involvement of the diaphragm and respiratory muscles. The findings suggest that phrenic nerve PNS could offer a viable treatment option for patients unresponsive to conventional therapies, warranting further research to establish its long-term efficacy and safety.

Dorsal root ganglion stimulation provides significant functional improvement from acute debilitating Crohn's disease: A novel use.

Crohn's disease is a chronic inflammatory bowel condition causing symptoms, notably pain, due to ongoing intestinal inflammation or complications like abscesses, strictures, and fistulas, which are common in IBD patients. Abdominal pain affects up to 60 % of IBD patients, irrespective of disease severity, prompting medical attention. Various medications like NSAIDs, antidepressants, antispasmodics, anticonvulsants, and opioids are used to manage pain, but they have limited effectiveness and potential side effects, even during remission. In this case, a 20-year-old Caucasian female college student [height 5'4″, weight 120lbs (54.4 kg)] with juvenile idiopathic arthritis and Crohn's disease experienced severe daily abdominal pain, negatively impacting her life. Despite a multimodal regimen, including gabapentin, nortriptyline, duloxetine, and acetaminophen, her pain persisted, significantly affecting her appetite, sleep, mood, activity level, and overall quality of life (QOL). To address this, dorsal root ganglion (DRG) stimulation was considered. The patient aimed for a 20 % pain reduction and improved QOL. Trial leads were placed along the T10 and T12 DRG, resulting in a 25 % pain reduction (8-6 out of 10) and substantial QOL improvement. She could eat, sleep without interruptions, walk longer distances, and be more active. The T12 lead was more effective than the T10, targeting upper abdomen stimulation. The patient and her mother were highly satisfied and opted for permanent implantation for the T11 and T12 DRG. While DRG stimulation was approved in 2016 for chronic pain, to our knowledge, this is the first reported case of its use in a patient with debilitating Crohn's disease.

Nerve-Targeted Surgical Treatments for Spasticity: A Narrative Review.

Spasticity is a potentially debilitating symptom of various acquired and congenital neurologic pathologies that, without adequate treatment, may lead to long-term disability, compromise functional independence, and negatively impact mental health. Several conservative as well as non-nerve targeted surgical strategies have been developed for the treatment of spasticity, but these may be associated with significant drawbacks, such as adverse side effects to medication, device dependence on intrathecal baclofen pumps, and inadequate relief with tendon-based procedures. In these circumstances, patients may benefit from nerve-targeted surgical interventions such as (i) selective dorsal rhizotomy, (ii) hyperselective neurectomy, and (iii) nerve transfer. When selecting the appropriate surgical approach, preoperative patient characteristics, as well as the risks and benefits of nerve-targeted surgical intervention, must be carefully evaluated. Here, we review the current evidence on the efficacy of these nerve-targeted surgical approaches for treating spasticity across various congenital and acquired neurologic pathologies.

Psilocybin and chronic neuropathic pain: a systematic review.

BACKGROUND/IMPORTANCE: Chronic pain affects many people globally, requiring alternative management strategies. Psilocybin is gaining attention for its potential in chronic pain management despite being classified as Schedule I. OBJECTIVE: This systematic review critically evaluates the evidence for psilocybin, a Schedule I substance, in the treatment of chronic pain. The exact purpose of the review is to assess the impact of psilocybin on chronic pain relief, focusing on dosing protocols, treated conditions, and patient outcomes. EVIDENCE REVIEW: A comprehensive review of PubMed, CINAHL, Web of Science, Cochrane Library, and EMBASE was conducted up to January 2024. Eligibility criteria included studies evaluating psilocybin for chronic pain management. The risk of bias was assessed using the MASTER (MethodologicAl STandards for Epidemiological Research) scale, and the strength of evidence was graded using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation). FINDINGS: The review identified 28 relevant studies focusing on dosing, treated conditions, and outcomes. The majority of the included studies (76.2%) were of low or very low quality. Several studies with moderate-to-low-quality evidence utilized a 0.14 mg/kg dosing protocol. The findings suggest promise for the use of psilocybin in chronic pain relief, though the quality of evidence is generally low. CONCLUSIONS: The current research shows potential for psilocybin as a treatment option for chronic pain relief. However, methodological issues and a lack of high-quality evidence underscore the need for further investigations with standardized protocols. Despite these limitations, the potential for psilocybin in chronic pain management is encouraging. PROSPERO REGISTRATION NUMBER: CRD42023493823.

Delayed-onset lumbosacral polyradiculitis following proton precision beam therapy for localized prostate cancer: A case report.

Introduction: In males, prostate cancer is the second most diagnosed cancer worldwide and the sixth leading cause of cancer death. Radiation therapy is a common treatment modality for prostate cancer but carries a multitude of adverse effects, ranging from radiation cystitis to post-radiation neuropathy. Proton beam therapy has gained attention as a valuable alternative, due to its improved precision with targeted dose delivery and reduced toxicity. However, the risk for radiation-induced complications, such as radiation-induced lumbar radiculopathy, is not fully understood and requires further investigation. Case presentation: We present a 68-year-old man with delayed-onset lumbosacral polyradiculitis following proton precision beam therapy for localized prostate cancer. The patient underwent proton therapy treatment for the prostate and seminal vesicles with favorable results and tumor remission. However, five months after completing radiation therapy, the patient presented with chronic lower extremity pain, weakness, and bilateral lower extremity paresthesias. MRI showed diffuse hyperintensity of bilateral L5-S3 nerve roots and an intramuscular edema-like signal involving the bilateral obturator externus and internus muscles, likely due to radiation. Additionally, EMG findings suggested the presence of chronic bilateral L5 radiculopathy. Conclusion: The clinical manifestation of delayed-onset radiation-induced lumbosacral plexopathy is a rare and uncommon complication of external beam radiation therapy that presents as radicular or myelopathic symptoms based on the location and severity of the inflammation. This case highlights the need for continued follow-up post-radiation and emphasizes the need for a comprehensive review of the oncological history of cancer patients.

Spinal cord stimulation may reduce lumbar radiculopathy in the setting of metastatic colon cancer.

Cancer pain has a substantial impact on the quality of life and functional capacity with a prevalence of up to 70 % in patients with advanced, metastatic, or terminal disease [1]. The WHO pain ladder has been used in practice to guide cancer pain management. A three-step ladder starts with NSAIDs and non-opioids for mild pain, weak opioids for mild to moderate pain and strong opioids for moderate to severe pain with the use of adjuvant medications such as TCAs and muscle relaxants at any stage for optimization (Fallon et al., Dec 2022) [2] We present a case of a patient with metastatic colon cancer who was admitted for intractable pain crisis and right sided L-5 radiculopathy secondary to epidural metastasis (Figs. 1 and 2). The patient's pain left her bedridden, unable to walk and remained refractory to an escalating intravenous opioid regimen and caudal epidural steroids. The patient subsequently underwent spinal cord stimulation (SCS) trial at level T-7 and achieved >80 % pain relief resulting in a markedly decreased opioid requirement and tremendous recovery of ambulatory function (Fig. 3). After sustained results, a permanent implant was placed at T-8 and patient remains discharged with functional restoration and continued pain improvement (Fig. 4). To our knowledge, this is a novel application of SCS for a refractory pain crisis secondary to a metastatic colon cancer induced radiculopathy presenting with severe functional impairment. As we transition away from opioid use, it is imperative as pain physicians, to investigate the potential of current as an alternative means of cancer pain management: a ubiquitous and challenging clinical conundrum.

Pedicle subtraction metallectomy with complex posterior reconstruction for fixed cervicothoracic kyphosis: illustrative case.

BACKGROUND: Iatrogenic cervical deformity is a devastating complication that can result from a well-intended operation but a poor understanding of the individual biomechanics of a patient's spine. Patient factors, such as bone fragility, high T1 slope, and undiagnosed myopathies often play a role in perpetuating a deformity despite an otherwise successful surgery. This imbalance can lead to significant morbidity and a decreased quality of life. OBSERVATIONS: A 55-year-old male presented to the authors' clinic with a chin-to-chest deformity and cervical myelopathy. He previously had an anterior C2-T2 fixation and a posterior C1-T6 instrumented fusion. He subsequently developed screw pullout at multiple levels, so the original surgeon removed all of the posterior hardware. The T1 cage (original corpectomy) severely subsided into the body of T2, generating an angular kyphosis that eventually developed a rigid osseous circumferential union at the cervicothoracic junction with severe cord compression. An anterior approach was not feasible; therefore, a 3-column osteotomy/fusion in the upper thoracic spine was planned whereby 1 of the T2 screws would need to be removed from a posterior approach for the reduction to take place. LESSONS: This case highlights the devastating effect of a hardware complication leading to a fixed cervical spine deformity and the complex decision making involved to safely correct the challenging deformity and restore function.

Surgical management of symptomatic vertebral hemangiomas: A case report and literature review.

BACKGROUND: Vertebral hemangiomas (VHs) are common benign tumors that only rarely become symptomatic. There is a paucity of data regarding their surgical management and outcomes. Here, we reported a case involving an aggressive cervical VH, discussed its surgical management and outcomes, and reviewed the literature. METHODS: We assessed the clinical, radiological, and surgical outcomes for a patient with an aggressive cervical VH. We also performed a systematic review of the literature according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to describe surgical outcomes for symptomatic VH. RESULTS: A total of 154 studies including 535 patients with VH were included in the study. The majority of patients were female (62.8%), the average age was 43 years, and the thoracic spine was most commonly involved (80.6%). Utilizing Odom's criteria, outcomes were excellent in 81.7% (95% CI 73.2-90.2) of cases. For those presenting with myelopathy (P = 0.045) or focal neurological deficits (P = 0.018), outcomes were less likely to be excellent. Preoperative embolization was not associated with excellent outcome (P = 0.328). CONCLUSION: Surgical outcomes for VH are predominantly favorable, but aggressive VHs have the potential to cause significant residual postoperative neurological morbidity.

Activation of p53 and destabilization of androgen receptor by combinatorial inhibition of MDM2 and MDMX in prostate cancer cells.

Castration-resistant prostate cancer (CRPC) frequently develops after initial standard radiation and androgen deprivation therapy, leaving patients with limited further treatment options. Androgen receptor (AR) is a transcription factor that plays a key role in the initiation and progression of prostate cancer. p53, a major tumor suppressor that is rarely mutated in early-stages of prostate cancer, is often deregulated during prostate cancer progression. Here, we report an unusual co-amplification of MDM2 and MDMX, two crucial negative regulators of p53, in CRPC datasets. We demonstrate that combinatorial inhibition of MDM2 and MDMX, with nutlin-3 and NSC207895 respectively, has a profound inhibitory effect on cell proliferation of androgen-responsive, wild-type TP53 gene carrying prostate cancer cells LNCaP and 22Rv1. We further show that the combinatorial inhibition of MDM2 and MDMX not only activates p53, but also decreases cellular levels of AR and represses its function. Additionally, co-expression of MDM2 and MDMX stabilizes AR. Together, our results indicate that combinatorial inhibition of MDM2 and MDMX may offer a novel compelling strategy for prostate cancer therapy.