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OBJECTIVE The aim of this study was to elucidate the long-term morbidity associated with untreated cerebral cavernous malformation (CCM). METHODS From a prospectively maintained database of patients with CCM, we assessed functional outcome as measured using the modified Rankin Scale (mRS) score at baseline and the last untreated follow-up evaluation. Disability was defined as an mRS score ≥ 3. Kaplan-Meier curves were used to assess the time to disability, and Cox proportional hazards models were used to determine risk factors for disability. Furthermore, the predictive performance of a previously published nomogram for morbidity in CCM was assessed. RESULTS The cohort consisted of 332 patients (58.4% female, mean age at diagnosis 44.5 years), with 19.8% having the familial form and 28.0% having a CCM located in the brainstem. Of 48 patients who presented with symptomatic hemorrhage (SH) and who did not undergo surgery or have a prospective SH, 27.1% had an mRS score ≥ 3 at diagnosis. By 1 year and 5 years, this improved to 6.2% and 4.7%, respectively. Over a mean follow-up duration of 6.6 years, 103 of 332 patients (31.0%) had one prospective SH and 48 (14.5%) had multiple prospective SHs. Patients with brainstem-located CCM had an 18.8% 5-year and 35.4% 10-year risk of disability compared with 4.1% and 7.5%, respectively, in patients with a nonbrainstem location (p < 0.0001). Multivariate analysis showed that a brainstem location, history of self-reported psychiatric disorder, and ≥ 2 SHs were predictive of disability at the last follow-up. External validation of a published nomogram demonstrated high specificity but limited sensitivity for predicting disability, with an area under the receiver operating curve of 0.687 for mRS scores ≥ 2 and 0.783 for mRS scores ≥ 3. CONCLUSIONS Most patients improved after a first hemorrhage, with the most improvement occurring in year 1. Disability increased with each SH. Disability was associated with 2 or more SHs, a brainstem location, and a self-reported psychiatric diagnosis. Ten-year disability risk with a nonbrainstem CCM location was < 8%.

BACKGROUND: Spinal cord involvement is infrequently reported in primary central nervous system vasculitis (PCNSV). This study describes the clinical findings, therapeutic responses, and outcomes of spinal cord involvement in a large cohort of patients with PCNSV. METHODS: We retrospectively studied 216 consecutive patients with PCNSV evaluated at the Mayo Clinic from 1983 to 2023. Spinal cord involvement was documented by histological examination or imaging. The clinical, laboratory, radiological, and pathological findings, along with management and outcomes, were compared between patients with and without spinal cord involvement. RESULTS: Of 216 patients, 10 (4.6%) had spinal cord involvement, with cerebral involvement in 9 cases. One patient (0.5%) had isolated spinal cord vasculitis. Histological evidence of vasculitis was found in all 10, with necrotizing vasculitis in 5 (50%). Magnetic resonance imaging showed thoracic abnormalities in 8 patients, cervical spine involvement in 2, conus medullaris involvement in 3, and cauda equina enhancement in 4. Compared with the 206 patients without spinal cord involvement, those with spinal cord vasculitis were more likely to present with paraparesis/tetraparesis ( P <0.001) and necrotizing vasculitis ( P =0.01) and less likely with hemiparesis ( P =0.006) and granulomatous vasculitis ( P =0.03). Patients with spinal cord involvement were more likely to have at least 1 relapse ( P <0.001) or more ( P <0.001). No differences between the 2 groups were observed regarding long-term remission, therapy response, and high disability scores (modified Rankin Scale score, 4–6) or death at last follow-up. Spinal cord involvement was associated with meningeal enhancement on brain imaging (odds ratio, 10.50) and the presence of lymphoma (odds ratio, 6.49), specifically Hodgkin lymphoma diagnosed simultaneously with PCNSV. Spinal involvement was negatively associated with increasing age (odds ratio, 0.64) and cerebral infarction on imaging (odds ratio, 0.08). CONCLUSIONS: Spinal cord involvement defines a distinct subset of patients with PCNSV.

ImportanceMyeloperoxidase is one of the most abundant peroxidase enzymes in activated myeloid cells. Myeloperoxidase inhibitors may have a clinical benefit in amyotrophic lateral sclerosis (ALS) by slowing neurodegeneration via reduced neuroinflammation and oxidative stress.ObjectiveTo determine the safety, tolerability, and efficacy of verdiperstat, a selective myeloperoxidase inhibitor, in ALS.Design, Settings, and ParticipantsVerdiperstat was tested as a regimen of the HEALEY ALS Platform Trial, a multicenter, double-blind, perpetual platform design, randomized clinical trial, with sharing of trial infrastructure and placebo data across multiple regimens. The study was conducted at 54 ALS referral centers across the US from July 2020 to April 2022. Adult participants with a diagnosis of clinically possible, probable, laboratory-supported probable, or definite ALS defined by the revised El Escorial criteria were randomized to verdiperstat or regimen-specific placebo. An additional group of participants concurrently randomized to placebo from other regimens was included in the analyses.InterventionsEligible participants were randomized in a 3:1 ratio to receive oral verdiperstat, 600 mg, twice daily or matching placebo for a planned placebo-controlled duration of 24 weeks.Main Outcomes and MeasuresThe primary efficacy outcome was change from baseline through week 24 in disease severity, as measured by a joint model of ALS Functional Rating Scale–Revised and survival, with the treatment effect quantified by the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression of verdiperstat relative to placebo.ResultsA total of 167 participants (mean [SD] age, 58.5 [11.4] years; 59 [35.3%] female; 108 [64.6%] male) were randomized to either verdiperstat (126 [75.4%]) or to placebo (41 [25.6%]). Among the participants randomized to the verdiperstat regimen, 130 (78%) completed the trial. The estimated DRR was 0.98 (95% credible interval, 0.77-1.24; posterior probability = 0.57 for slowing of disease progression [DRR &amp;lt;1]). Verdiperstat was estimated to slow progression by 2% vs placebo (95% credible interval, −23% to 24%; posterior probability 0.57). Verdiperstat was overall safe and well tolerated. Common adverse events in the verdiperstat group were nausea, insomnia, and elevated thyrotropin levels.Conclusions and RelevanceResults demonstrate that treatment with verdiperstat was unlikely to alter disease progression in ALS.Trial RegistrationClinical Trial Identifiers: NCT04297683 and NCT04436510