John Robinson Singleton

The lack of approved therapies for N-methyl-d-aspartate receptor (NMDAR) encephalitis has contributed to substantial variability in treatment. Inebilizumab is a humanized anti-CD19 monoclonal antibody that can be administered intravenously. Inebilizumab may be an efficacious treatment for patients with NMDAR encephalitis, with the potential to achieve early robust and sustained suppression CD19⁺ plasmablasts, some plasma cells, and NMDAR autoantibodies, with the potential to improve short-term and long-term outcomes in patients with NMDAR encephalitis. The ExTINGUISH trial is a multisite, phase 2B, randomized, double-blind, placebo-controlled trial designed to evaluate the safety and efficacy of inebilizumab 300 mg for the acute treatment of participants with moderate-to-severe NMDAR encephalitis. ExTINGUISH will randomize 116 patients across the United States and Europe. Participants will receive standard first-line immunotherapies (intravenous steroids and intravenous immunoglobulins and/or plasma exchange) before randomization (1:1). In addition, cyclophosphamide rescue therapy will be offered to participants with persistent moderate-to-severe disease 6 weeks after randomization. Primary outcomes will be measured 16 weeks from randomization using the change in the adapted ExTINGUISH modified Rankin scale and accepted safety measures in 32 weeks. Secondary outcomes will be measured up to 96 weeks and include comprehensive neuropsychological tests, bedside cognitive screening tools, and quality-of-life/functional indices. Clinical data will be combined with blood and CSF biomarkers of immune activation to inform putative biologic contributors to outcomes (exploratory outcomes). Study operations are supported by the National Institute of Neurological Disorders and Stroke–supported Network for Excellence in Neuroscience Clinical Trial (NeuroNEXT) infrastructure. The ExTINGUISH trial will determine the safety and efficacy of inebilizumab as a treatment of NMDAR encephalitis while evaluating the utility of clinical, cognitive, and quality-of-life outcome measures and supporting standardized collection and measurement of biofluid biomarkers. These innovations will inform development of future treatments and trials for patients with NMDAR encephalitis and other types of autoimmune encephalitis. The ExTINGUISH trial opened to enrollment of adult patients (older than 18 years) in 2022 and pediatric patients (older than 12 years) in 2024; enrollment is ongoing.

: The cutaneous mechanisms that trigger spontaneous neuropathic pain in diabetic peripheral neuropathy (PDPN) are far from clear. Two types of nociceptors are found within the epidermal and dermal skin layers. Small-diameter lightly myelinated Aδ and unmyelinated C cutaneous mechano and heat-sensitive (AMH and CMH) and C mechanoinsensitive (CMi) nociceptors transmit pain from the periphery to central nervous system. AMH and CMH fibers are mainly located in the epidermis, and CMi fibers are distributed in the dermis. In DPN, dying back intra-epidermal AMH and CMH fibers leads to reduced pain sensitivity, and the patients exhibit significantly increased pain thresholds to acute pain when tested using traditional methods. The role of CMi fibers in painful neuropathies has not been fully explored. Microneurography has been the only tool to access CMi fibers and differentiate AMH, CMH, and CMi fiber types. Due to the complexity, its use is impractical in clinical settings. In contrast, a newly developed diode laser fiber selective stimulation (DLss) technique allows to safely and selectively stimulate Aδ and C fibers in the superficial and deep skin layers. DLss data demonstrate that patients with painful DPN have increased Aδ fiber pain thresholds, while C-fiber thresholds are intact because, in these patients, CMi fibers are abnormally spontaneously active. It is also possible to determine the involvement of CMi fibers by measuring the area of DLss-induced neurogenic axon reflex flare. The differences in AMH, CMH, and CMi fibers identify patients with painful and painless neuropathy. In this review, we will discuss the role of CMi fibers in PDPN.

Background: Peripheral neuropathy is among the most common complications of diabetes, but a phenotypically identical distal sensory predominant, painful axonopathy afflicts patients with prediabetic metabolic syndrome, exemplifying a spectrum of risk and continuity of pathogenesis. No pharmacological treatment convincingly improves neuropathy in the setting of metabolic syndrome, but evolving data suggest that exercise may be a promising alternative.Objective: The aim of the study was to review in depth the current literature regarding exercise treatment of metabolic syndrome neuropathy in humans and animal models, highlight the diverse mechanisms by which exercise exerts beneficial effects, and examine adherence limitations, safety aspects, modes and dose of exercise.Results: Rodent models that recapitulate the organismal milieu of prediabetic metabolic syndrome and the phenotype of its neuropathy provide a strong platform to dissect exercise effects on neuropathy pathogenesis. In these models, exercise reverses hyperglycemia and consequent oxidative and nitrosative stress, improves microvascular vasoreactivity, enhances axonal transport, ameliorates the lipotoxicity and inflammatory effects of hyperlipidemia and obesity, supports neuronal survival and regeneration following injury, and enhances mitochondrial bioenergetics at the distal axon. Prospective human studies are limited in scale but suggest exercise to improve cutaneous nerve regenerative capacity, neuropathic pain, and task-specific functional performance measures of gait and balance. Like other heath behavioral interventions, the benefits of exercise are limited by patient adherence.Conclusion: Exercise is an integrative therapy that potently reduces cellular inflammatory state and improves distal axonal oxidative metabolism to ameliorate features of neuropathy in metabolic syndrome. The intensity of exercise need not improve cardinal features of metabolic syndrome, including weight, glucose control, to exert beneficial effects.

SRX246 is a vasopressin (AVP) 1a receptor antagonist that crosses the blood-brain barrier. It reduced impulsive aggression, fear, depression and anxiety in animal models, blocked the actions of intranasal AVP on aggression/fear circuits in an experimental medicine fMRI study and demonstrated excellent safety in Phase 1 multiple-ascending dose clinical trials. The present study was a 3-arm, multicenter, randomized, placebo-controlled, double-blind, 12-week, dose escalation study of SRX246 in early symptomatic Huntington’s disease (HD) patients with irritability. Our goal was to determine whether SRX246 was safe and well tolerated in these HD patients given its potential use for the treatment of problematic neuropsychiatric symptoms. Participants were randomized to receive placebo or to escalate to 120 mg twice daily or 160 mg twice daily doses of SRX246. Assessments included standard safety tests, the Unified Huntington’s Disease Rating Scale (UHDRS), and exploratory measures of problem behaviors. The groups had comparable demographics, features of HD and baseline irritability. Eighty-two out of 106 subjects randomized completed the trial on their assigned dose of drug. One-sided exact-method confidence interval tests were used to reject the null hypothesis of inferior tolerability or safety for each dose group vs. placebo. Apathy and suicidality were not affected by SRX246. Most adverse events in the active arms were considered unlikely to be related to SRX246. The compound was safe and well tolerated in HD patients and can be moved forward as a candidate to treat irritability and aggression.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and disabling adverse effect of lifesaving neurotoxic chemotherapy.^1-3 Depending on the agent, 30% to 70% of people receiving neurotoxic chemotherapy develop neuropathy.^4,5 The taxanes, platinums, and vinca alkaloids are the agents most commonly associated with CIPN. The risk of developing CIPN increases with both the total cumulative dose of chemotherapy and the exposure to multiple neurotoxic agents.^5-8 Chemotherapy-induced peripheral neuropathy most commonly causes a length-dependent sensory-predominant axonal neuropathy, although the platinums and taxanes are unique in that the hands and feet can be affected simultaneously.^5,9

Length-dependent neuropathy is the most common and costly complication of diabetes and frequently causes injury primarily to small-diameter cutaneous nociceptive fibers. Not only persistent hyperglycemia but also metabolic, endocrine, and inflammatory effects of obesity and dyslipidemia appear to play an important role in the development of diabetic neuropathy. Rational therapies aimed at direct control of glucose or its increased entry into the polyol pathway, oxidative or nitrosative stress, advanced glycation end product formation or signaling, microvascular ischemia, or adipocyte-derived toxicity have each failed in human trials of diabetic neuropathy. Aerobic exercise produces salutary effects in many of these pathogenic pathways simultaneously and, in both animal models and human trials, has been shown to improve symptoms of neuropathy and promote re-growth of cutaneous small-diameter fibers. Behavioral reduction in periods of seated, awake inactivity produces multimodal metabolic benefits similar to exercise, and the two strategies when combined may offer sustained benefit to peripheral nerve function.

Objective: Unmyelinated cutaneous axons are vulnerable to physical and metabolic injury, but also capable of rapid regeneration. This balance may help determine risk for peripheral neuropathy associated with diabetes or metabolic syndrome. Capsaicin application for 48 hours induces cutaneous fibers to die back into the dermis. Regrowth can be monitored by serial skin biopsies to determine intraepidermal nerve fiber density (IENFD). We used this capsaicin axotomy technique to examine the effects of exercise on cutaneous regenerative capacity in the setting of metabolic syndrome.Methods: Baseline ankle IENFD and 30‐day cutaneous regeneration after thigh capsaicin axotomy were compared for participants with type 2 diabetes (n = 35) or metabolic syndrome (n = 32) without symptoms or examination evidence of neuropathy. Thirty‐six participants (17 with metabolic syndrome) then joined twice weekly observed exercise and lifestyle counseling. Axotomy regeneration was repeated in month 4 during this intervention.Results: Baseline distal leg IENFD was significantly reduced for both metabolic syndrome and diabetic groups. With exercise, participants significantly improved exercise capacity and lower extremity power. Following exercise, 30‐day reinnervation rate improved (0.051 ± 0.027 fibers/mm/day before vs 0.072 ± 0.030 after exercise, p = 0.002). Those who achieved improvement in more metabolic syndrome features experienced a greater degree of 30‐day reinnervation (p < 0.012).Interpretation: Metabolic syndrome was associated with reduced baseline IENFD and cutaneous regeneration capacity comparable to that seen in diabetes. Exercise‐induced improvement in metabolic syndrome features increased cutaneous regenerative capacity. The results underscore the potential benefit to peripheral nerve function of a behavioral modification approach to metabolic improvement. ANN NEUROL 2015;77:146–153

Early diabetic neuropathy is characterized by loss of unmyelinated axons, resulting in pain, numbness, and progressive decline in intraepidermal nerve fiber density. Patients with type 2 diabetes, without neuropathy, were assigned to quarterly lifestyle counseling (N = 40) or structured, supervised weekly exercise (N = 60) for 1 year. Distal leg IENFD significantly increased in the exercise cohort and remained unchanged in the counseling cohort (1.5 ± 3.6 vs. −0.1 ± 3.2 fibers/mm, P = 0.03). These results suggest preclinical injury to unmyelinated axons is potentially reversible, and that IENFD may be a responsive biomarker useful in future neuropathy prevention clinical trials.