Inhibition of CD40L with Frexalimab in Multiple Sclerosis.

BACKGROUND: The CD40-CD40L costimulatory pathway regulates adaptive and innate immune responses and has been implicated in the pathogenesis of multiple sclerosis. Frexalimab is a second-generation anti-CD40L monoclonal antibody being evaluated for the treatment of multiple sclerosis. METHODS: In this phase 2, double-blind, randomized trial, we assigned, in a 4:4:1:1 ratio, participants with relapsing multiple sclerosis to receive 1200 mg of frexalimab administered intravenously every 4 weeks (with an 1800-mg loading dose), 300 mg of frexalimab administered subcutaneously every 2 weeks (with a 600-mg loading dose), or the matching placebos for each active treatment. The primary end point was the number of new gadolinium-enhancing T1-weighted lesions seen on magnetic resonance imaging at week 12 relative to week 8. Secondary end points included the number of new or enlarging T2-weighted lesions at week 12 relative to week 8, the total number of gadolinium-enhancing T1-weighted lesions at week 12, and safety. After 12 weeks, all the participants could receive open-label frexalimab. RESULTS: Of 166 participants screened, 129 were assigned to a trial group; 125 participants (97%) completed the 12-week double-blind period. The mean age of the participants was 36.6 years, 66% were women, and 30% had gadolinium-enhancing lesions at baseline. At week 12, the adjusted mean number of new gadolinium-enhancing T1-weighted lesions was 0.2 (95% confidence interval [CI], 0.1 to 0.4) in the group that received 1200 mg of frexalimab intravenously and 0.3 (95% CI, 0.1 to 0.6) in the group that received 300 mg of frexalimab subcutaneously, as compared with 1.4 (95% CI, 0.6 to 3.0) in the pooled placebo group. The rate ratios as compared with placebo were 0.11 (95% CI, 0.03 to 0.38) in the 1200-mg group and 0.21 (95% CI, 0.08 to 0.56) in the 300-mg group. Results for the secondary imaging end points were generally in the same direction as those for the primary analysis. The most common adverse events were coronavirus disease 2019 and headaches. CONCLUSIONS: In a phase 2 trial involving participants with multiple sclerosis, inhibition of CD40L with frexalimab had an effect that generally favored a greater reduction in the number of new gadolinium-enhancing T1-weighted lesions at week 12 as compared with placebo. Larger and longer trials are needed to determine the long-term efficacy and safety of frexalimab in persons with multiple sclerosis. (Funded by Sanofi; ClinicalTrials.gov number, NCT04879628.).

Placebo-Controlled Trial of an Oral BTK Inhibitor in Multiple Sclerosis.

BACKGROUND: Bruton's tyrosine kinase (BTK) regulates the functions of B cells and myeloid cells that are implicated in the pathogenesis of multiple sclerosis. Evobrutinib is a selective oral BTK inhibitor that has been shown to inhibit B-cell activation both in vitro and in vivo. METHODS: In this double-blind, randomized, phase 2 trial, we assigned patients with relapsing multiple sclerosis to one of five groups: placebo, evobrutinib (at a dose of 25 mg once daily, 75 mg once daily, or 75 mg twice daily), or open-label dimethyl fumarate (DMF) as a reference. The primary end point was the total (cumulative) number of gadolinium-enhancing lesions identified on T1-weighted magnetic resonance imaging at weeks 12, 16, 20, and 24. Key secondary end points included the annualized relapse rate and change from baseline in the score on the Expanded Disability Status Scale (EDSS). RESULTS: A total of 267 patients were randomly assigned to a trial group. The mean (±SD) total number of gadolinium-enhancing lesions during weeks 12 through 24 was 3.85±5.44 in the placebo group, 4.06±8.02 in the evobrutinib 25-mg group, 1.69±4.69 in the evobrutinib 75-mg once-daily group, 1.15±3.70 in the evobrutinib 75-mg twice-daily group, and 4.78±22.05 in the DMF group. The baseline adjusted rate ratios for the total number of lesions over time as compared with placebo were 1.45 in the evobrutinib 25-mg group (P = 0.32), 0.30 in the evobrutinib 75-mg once-daily group (P = 0.005), and 0.44 in the evobrutinib 75-mg twice-daily group (P = 0.06). The unadjusted annualized relapse rate at week 24 was 0.37 in the placebo group, 0.57 in the evobrutinib 25-mg group, 0.13 in the evobrutinib 75-mg once-daily group, 0.08 in the evobrutinib 75-mg twice-daily group, and 0.20 in the DMF group. There was no significant effect of trial group on the change from baseline in the EDSS score. Elevations in liver aminotransferase values were observed with evobrutinib. CONCLUSIONS: Patients with relapsing multiple sclerosis who received 75 mg of evobrutinib once daily had significantly fewer enhancing lesions during weeks 12 through 24 than those who received placebo. There was no significant difference with placebo for either the 25-mg once-daily or 75-mg twice-daily dose of evobrutinib, nor in the annualized relapse rate or disability progression at any dose. Longer and larger trials are required to determine the effect and risks of evobrutinib in patients with multiple sclerosis. (Funded by EMD Serono; ClinicalTrials.gov number, NCT02975349.).

European Stroke Organisation certification of stroke units and stroke centres.

To improve quality and to overcome the wide discrepancies in stroke care both within- and between European countries, the European Stroke Organisation Executive Committee initiated in 2007 activities to establish certification processes for stroke units and stroke centres. The rapidly expanding evidence base in stroke care provided the mandate for the European Stroke Organisation Stroke Unit-Committee to develop certification procedures for stroke units and stroke centres with the goals of setting standards for stroke treatment in Europe, improving quality and minimising variation. The purpose of this article is to present the certification criteria and the auditing process for stroke units and stroke centres that aim to standardise and harmonise care for stroke patients, and hence become members of the European Stroke Organisation Stroke Unit and Stroke Centre network. Standardised application forms and guidelines for national and international auditors have been developed and updated by members of the European Stroke Organisation Stroke Unit-Committee. Key features are availability of trained personnel, diagnostic equipment, acute treatment and collaboration with other stroke-caregivers. After submission, the application is reviewed by one national and two international auditors. Based on their reports, the Stroke Unit-Committee will make a final decision. Validating on-site visits for a subset of stroke units and stroke centres are planned. We herein describe a novel, European Stroke Organisation-based online certification process of stroke units and stroke centres. This is a major step forward towards high-quality stroke care across Europe. The additional value by connecting high-quality European Stroke Organisation Stroke Unit and Stroke Centre is facilitation of future collaboration and research activities, enabling building and maintenance of a high-quality stroke care network in Europe.

Is herpes simplex a systemic disease?

Orofacial herpes simplex virus infections are usually caused by herpes simplex virus 1 (HSV-1), and HSV-2 infections have been accepted as a sexually transmitted disease. HSV establishes a latent infection in the dorsal root ganglia of the host and remains there for the rest of life. HSV affects mainly skin and genitalia, although in immunocompromised patients it may cause local infection with vast skin involvement, chronic herpetic ulcers, or widespread mucous membrane damage, as well as systemic infections localized in the central and peripheral nervous systems, gastrointestinal tract, and ocular system. Usually, HSV infections are in the domain of dermatology, but the accumulating facts for localization of the disease in many systems of the human body give us the possibility to pose the question: Is herpes simplex a systemic disease?

Temporal modulation of cerebral hemodynamics under prefrontal challenge in schizophrenia: a transcranial Doppler sonography study.

Transcranial Doppler sonography (TCD) is a non-invasive method to assess cerebral blood flow velocity (CBFV) and hence cerebral blood flow during cognitive activation. Major cognitive dysfunctions have been consistently reported in patients with schizophrenia, and important deficits have been observed with respect to prefrontal functions. However, prefrontal activation in schizophrenics has not been investigated with TCD despite its potential to examine short-term changes of cerebral blood flow. The Wisconsin Card Sorting Test (WCST) and the Tower of Hanoi puzzle were administered to 11 right-handed schizophrenics and 20 healthy controls. The middle and anterior cerebral arteries were pairwise insonated. Schizophrenics showed decreased CBFV during the initial phase of both prefrontal functions and the steady-state phase of the Tower of Hanoi. In healthy controls, there was a succession of three significantly different phases of mean CBFV during the Tower of Hanoi, and there was no such modulation in schizophrenics. Immediately after category shift in the WCST, there was an increase of mean CBFV in healthy controls, but not in schizophrenics. In conclusion, transcranial Doppler sonography was able to detect differing specific alterations of CBFV during two prefrontal tasks in healthy controls and patients with schizophrenia. Importantly, the results of this study imply a degraded pattern of CBFV changes over time in schizophrenia during prefrontal activation.

Herpes zoster as a systemic disease.

Herpes zoster (shingles, zona) is a viral infection commonly affliccting the skin and the nervous system with an overall occurring rate of 3 to 5 cases per 1000 persons per year, with higher rates in middle or later life. With the advancement of medicine, more and more case reports have started to emerge showing different incidences of VZV, some new localizations, clinical presentations, and complications, which break the well-known fact that "VZV affects the skin and nervous system." Skin lesions are the most important ones for the early and exact diagnosis of herpes zoster (HZ), due to its visibility and well-defined clinical picture of lesions. The most frequent condition following the acute herpes zoster eruption is postherapeutic neuralgia (PHN). There have been other reports of the disease with otorinolaryngologic complications and ophthalmologic ones, such as ophthalmoparesis/plegia. There have also been reports of delayed contralateral hemiparesis/hemiplegia following the infection, as a manifestation of vaculitis due to a direct VZV invasion of the cerebral arteries. Encephalitis and destructive myelitis is similarly rare, but a serious complication. Some authors found that patients with inflammatory bowel disease are at a significantly increased risk for herpes zoster. As a gastroenterologic complication, there have been several instances of HZV infection with symptoms resembling an acute abdomen. The diagnosis is hard to pinpoint, and a vast array of examinations are required to identify it, sometimes even posthumously. Nephrologic representations and complications have also been reported. With more and more skin diseases being acknowledged as systemic ones, this viral infection is a more likely candidate for the same title.

Bioequivalence of a novel high-dose oral formulation of alpha-dihydroergocryptine.

The plasma pharmacokinetics of alpha-dihydroergocryptine (DHEC, CAS 14271-05-7) were investigated in 24 patients with Parkinson disease after the administration of repeated oral doses of 40 mg DHEC twice daily by means of a novel 40 mg DHEC tablet (Almirid 40 mg test T) and an established 20 mg DHEC tablet (Almirid 20 mg - reference R). The trial was conducted according to a randomised, controlled, open, within-subject cross-over design; steady-state was established by means of a stepwise up-titration from 5 to 40 mg b.i.d. from day D01 to D19; investigational treatments (40 mg DHEC b.i.d. by means of formulation R and T) were administered on day D20 and D21 according to a randomised, period-balanced within-subject cross-over; treatment with DHEC was down-titrated in stepwise fashion from day D22 to D34. Morning doses of 2 x 20 mg DHEC (reference) yielded a fast and relatively short lasting peak with a geometric mean Cmax of 2157 pg/mL (CV: 0.978) after a median tmax of 1.00 h. Cmin throughout the first 12 h was on average 189 pg/mL (CV: 0.908). There was a quite distinct diurnal effect: evening doses of 2 x 20 mg DHEC (treatment R), yielded a relatively lower exposure with geometric mean Cmax, Cav- and Cmin-values of 800 pg/mL (CV: 0.870), 389 pg/mL (0.813) and 177 pg/mL (CV: 0.942). In contrast, there was relatively little within-subject distinction between the two formulations: for the day profile after the morning dose, the estimated ratios of the true means (Pr:R) for Cmax Cmin and Cav were 1.18 (90% CI: 0.96 to 1.43 - CVm: 0.394), 0.96 (90% CI: 0.86 to 1.09 - CVm: 0.230) and 1.06 (90% CI: 0.93 to 1.21 - CVm: 0.254); for the night profile after the evening dose, the estimated ratio of the true means (muT:muR) for Cmax, Cmin and Cav were 1.11 (90% CI: 0.91 to 1.35 - CVm: 0.395), 1.07 (90% CI: 0.95 to 1.20 - CVm: 0.232) and 1.07 (90% CI: 0.95 to 1.20 - CVm: 0.220). In view of important medical-ethical constraints not to expose an unreasonably high number of subjects, these findings could be accepted as a sufficient demonstration of bioequivalence.

Duplex sonographic criteria for measuring carotid stenoses.

PURPOSE: The aim of this retrospective study was to determine optimal duplex sonographic criteria for use in our institution for diagnosing severe carotid stenoses and to correlate those findings with angiographic measurements obtained by the European Carotid Surgery Trial (ECST), North American Symptomatic Carotid Endarterectomy Trial (NASCET), and Common Carotid (CC) methods of grading carotid stenoses. METHODS: We analyzed the angiographic data using the ECST, NASCET, and CC methods and compared the results with the duplex sonographic findings. We then calculated the sensitivity, specificity, positive and negative predictive values, and accuracy of the duplex sonographic method. Taking these parameters into account, the optimal intrastenotic peak systolic velocity (PSV) and end diastolic velocity (EDV) were derived for diagnosing severe stenoses according to the 3 angiographic methods. RESULTS: Optimal PSV and EDV values for diagnosing a 70% or greater stenosis in our laboratory were as follows: with the NASCET method of angiographic grading of stenoses, PSV 220 cm/second or greater and EDV 80 cm/second or greater, and with the ECST and CC methods, PSV 190 cm/second or greater, and EDV 65 cm/second or greater. The optimal PSV and EDV for diagnosing a stenosis of 80% or greater with the ECST grading method were 215 cm/second or greater and 90 cm/second or greater, respectively. CONCLUSIONS: Duplex sonography is a sensitive and accurate tool for evaluating severe carotid stenoses. Optimal PSVs and EDVs vary according to the angiographic method used to grade the stenosis. They are similar for stenoses 70% or greater with the NASCET method and for stenoses 80% or greater with the ECST method.