Exploring psychedelic-assisted therapy in the treatment of functional seizures: A review of underlying mechanisms and associated brain networks.

Functional seizures (FS), the most common subtype of functional neurological disorder (FND), cause serious neurological disability and significantly impact quality of life. Characterized by episodic disturbances of functioning that resemble epileptic seizures, FS coincide with multiple comorbidities and are treated poorly by existing approaches. Novel treatment approaches are sorely needed. Notably, mounting evidence supports the safety and efficacy of psychedelic-assisted therapy (PAT) for several psychiatric conditions, motivating investigations into whether this efficacy also extends to neurological disorders. Here, we synthesize past empirical findings and frameworks to construct a biopsychosocial mechanistic argument for the potential of PAT as a treatment for FS. In doing so, we highlight FS as a well-defined cohort to further understand the large-scale neural mechanisms underpinning PAT. Our synthesis is guided by a complexity science perspective which we contend can afford unique mechanistic insight into both FS and PAT, as well as help bridge these two domains. We also leverage this perspective to propose a novel analytic roadmap to identify markers of FS diagnostic specificity and treatment success. This endeavor continues the effort to bridge clinical neurology with psychedelic medicine and helps pave the way for a new field of psychedelic neurology.

Switch to generic formulation of temozolomide results in statistically significant increase in grade 3 and 4 bone marrow toxicity in glioma patients in the province of Alberta.

Background: Temozolomide (TMZ) is an oral, systemic chemotherapy used chiefly for treating high-grade glioma. Due to the rising costs of systemic chemotherapy, many jurisdictions have replaced brand name with generic formulations. The aim of this study was to determine whether or not there was difference in the incidence of grade 3 or 4 bone marrow toxicity and median overall survival in patients treated with brand name versus generic TMZ in the province of Alberta, Canada. The province suspended the use of generic TMZ based on preliminary data pointing to excess toxicity. Methods: This multicenter, retrospective study included data from patients with newly diagnosed high-grade glioma that received treatment with TMZ in Alberta. Multivariate logistic regression analysis was performed to determine the association between grade 3 or 4 toxicity to generic versus brand name TMZ exposure, ECOG score, and age. Kaplan-Meier survival estimates and log-rank testing were used to determine differences in overall survival between the brand name and generic TMZ cohorts, as well as the cytopenic versus non-cytopenic patients. Furthermore, a screening analysis for grade 3 or 4 bone marrow toxicity was conducted on all de novo glioma patients treated with brand name TMZ after Alberta preemptively stopped generic TMZ. Results: Grade 3 or 4 neutropenia and thrombocytopenia were observed in 15% and 19% of patients treated with generic TMZ (n = 156) as compared to 3% and 5% of patients (n = 100) treated with brand name TMZ-treated patients; P= .003 and .001. A trend toward increased median overall survival in glioblastoma patients treated with generic TMZ (13.7 months) versus brand name (15.8 months, P = .178.) was also observed through meeting statistical significance. Based on these results, the province stopped the use of generic TMZ and reverted to the Merck TMZ. An initial review of all new glioma patients (n = 89) treated with Merck TMZ since the province stopped the generic drug demonstrated 3.4% and 10.1% grade 3 or 4 neutropenia, respectively. Conclusions: The statistically significant difference in toxicity profile has prompted the province of Alberta to replace generic TMZ with brand name TMZ in high-grade glioma patients pending more detailed analysis. Our study provides evidence supporting the importance of conducting prospective studies on long-term safety for generic chemotherapies.

Management of Bevacizumab-Induced Proteinuria Using an Angiotensin Receptor Blocker (ARB) in a Neurofibromatosis Type 2 (NF-2) Patient With Vestibular Schwannoma.

Neurofibromatosis type 2 (NF-2) is a genetic condition that by definition includes bilateral vestibular schwannoma, a non-malignant lesion also known as acoustic neuroma. Patients often develop hearing impairment and hearing loss as a result of the involvement of the vestibulocochlear nerve bilaterally as well as attempts at surgical repair. A common treatment for NF-2-mediated schwannoma is the antiangiogenic agent, bevacizumab. In many cases, patients require prolonged and even lifelong treatment with bevacizumab to control schwannoma growth. However, long-term use of bevacizumab can be associated with multiple side effects including hypertension and proteinuria including nephrotic syndrome (>3g of protein excreted in the urine in 24 hours). In these situations, the challenge with discontinuing prolonged bevacizumab can be rapid tumor growth and worsening hearing loss. Pre-clinical data suggests that hearing loss can be prevented following treatment with the angiotensin receptor blocker (ARB), losartan, in an animal model of NF-2. ARBs are already established in nephrology guidelines to treat proteinuria and hypertension. Here, we present a patient with NF-2 who developed nephrotic syndrome while on bevacizumab. Attempts to discontinue bevacizumab resulted in near-immediate hearing loss. Treatment with the ARB telmisartan together with bevacizumab resulted in improved hearing, reduced proteinuria, and controlled hypertension.

Case report: Improvement in refractory functional seizures, depression, and quality of life with ketamine-assisted therapy.

Functional seizures, a primary subtype of functional neurological disorder (FND), are a known cause of serious neurological disability with an increasing awareness of their impact amongst the neuroscience community. Situated at the intersection of neurology and psychiatry, FND is characterized by a range of alterations in motor, sensory or cognitive performance, such as abnormal movements, limb weakness, and dissociative, seizure-like episodes. Functional seizures are known, in part, to have psychological underpinnings; however, the lack of effective and consistent treatment options requires research and novel approaches to better understand the etiology, diagnosis and what constitutes a successful intervention. Ketamine, a selective blocker of the N-methyl-D-aspartate receptor, has a well-established safety and efficacy profile. In recent years, ketamine-assisted therapy has shown increasing potential for treating a broad range of psychiatric conditions, building on its demonstrated rapid-acting antidepressant effects. Here we present a 51-year-old female with refractory daily functional seizures leading to significant disability and a medical history significant for major depressive disorder (MDD) and posttraumatic stress disorder (PTSD). After unsuccessful treatment attempts, the patient underwent a novel protocol with ketamine-assisted therapy. After 3 weeks of ketamine-assisted therapy followed by 20 weeks of intermittent ketamine treatment and ongoing integrative psychotherapy, the patient's seizures were significantly reduced in frequency and severity. She experienced significant improvements in depressive symptoms and functional ability scores. To our knowledge, this is the first reported case describing improvement in functional seizures following ketamine-assisted therapy. While rigorous studies are needed, this case report encourages further investigation of ketamine-assisted therapy for functional seizures and other functional neurological symptoms.

A previously unrecognized kanosamine biosynthesis pathway in Bacillus subtilis.

The ntd operon in Bacillus subtilis is essential for biosynthesis of 3,3'-neotrehalosadiamine (NTD), an unusual nonreducing disaccharide reported to have antibiotic properties. It has been proposed that the three enzymes encoded within this operon, NtdA, NtdB, and NtdC, constitute a complete set of enzymes required for NTD synthesis, although their functions have never been demonstrated in vitro. We now report that these enzymes catalyze the biosynthesis of kanosamine from glucose-6-phosphate: NtdC is a glucose-6-phosphate 3-dehydrogenase, NtdA is a pyridoxal phosphate-dependent 3-oxo-glucose-6-phosphate:glutamate aminotransferase, and NtdB is a kanosamine-6-phosphate phosphatase. None of these enzymatic reactions have been reported before. This pathway represents an alternate route to the previously reported pathway from Amycolatopsis mediterranei which derives kanosamine from UDP-glucose.