Citations

Abstract Purpose/Background This is the second part of a 2-part article that proposes improving the United States (US) clozapine package insert. Part II focuses on fatal outcomes and the 5 boxed warnings, 4 specifically for clozapine: severe neutropenia, seizure, orthostatic hypotension and myocarditis, and 1 for all antipsychotics (elderly with dementia). Methods US reports to the World Health Organization's global pharmacovigilance database were analyzed from clozapine's introduction to January 15, 2023. Findings/Results The US was the top reporter worldwide for clozapine with 56,003 reports and 9587 associated fatal outcomes. The 4 clozapine boxed warnings were associated with 534 fatal outcomes (218 with severe neutropenia, 131 with seizures, 125 with orthostasis, 36 with myocarditis, 24 with cardiomyopathy, and 0 with mitral valve prolapse). With no boxed warnings, pneumonia was associated with 674 fatal outcomes and increased white blood cell count (a sign of infection) with 596 fatal outcomes. After considering overlaps, pneumonia and increases in white blood cell count explained 900 fatalities, or 9.4% of 9587 fatal outcomes. The Food and Drug Administration continues to focus on severe neutropenia which was associated with only 218 or 2.3% of fatal outcomes, whereas 97.7% of fatal outcomes reported in US clozapine-treated patients had another cause. Implications/Conclusions To help prevent future deaths in clozapine-treated patients, the clozapine package insert should focus on fatal outcomes during infections. Part II offers detailed solutions regarding current boxed warnings and lack of a warning for pneumonia and other infections. The Supplementary Material includes letters of support from 124 non-US clozapine experts from 44 countries/regions who support Parts I and II.

ABSTRACTBackground and AimsNerve conduction studies (NCS) are integral to diagnosing chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), but their role in predicting treatment outcomes remains underexplored. This study evaluates NCS changes at first follow‐up (first NCS changes) as predictors of treatment success in CIDP, focusing on their correlation with clinical outcomes over time.MethodsNewly diagnosed CIDP patients meeting the 2021 EAN/PNS criteria were retrospectively evaluated. Baseline and first follow‐up NCS parameters were compared with clinical outcomes, assessed by the Neuropathy Impairment Score (NIS) and Inflammatory Neuropathy Cause and Treatment (INCAT) disability score. All patients received first‐line immunotherapy (intravenous immunoglobulin, corticosteroids, or plasma exchange).ResultsOf 39 treated patients, 26 (66.7%) were responders based on improving NIS trends, while 13 (33.3%) were nonresponders. Responders showed significant improvements at the first follow‐up in fibular compound muscle action potential (CMAP) amplitude, ulnar CMAP amplitude, summated CMAP amplitudes, and fibular motor conduction velocity. Changes in fibular CMAP amplitude consistently correlated with NIS (R = −0.8 to −0.6, p ≤ 0.004) and INCAT disability score improvements (R = −0.6 to −0.3, p ≤ 0.032) across all follow‐up intervals up to 60 months. Ulnar and summated CMAP amplitude changes also correlated with clinical outcomes, though their associations were less sustained than those of fibular CMAP amplitude.InterpretationThe first change in fibular CMAP amplitude is a reliable biomarker for predicting CIDP treatment response, with ulnar and summated CMAP amplitudes as alternatives when the fibular response is absent. Our findings highlight the utility of first NCS changes in monitoring and predicting treatment outcomes in CIDP.

OBJECTIVE The purpose of this study was to determine risk factors for distal junctional failure (DJF) following three-column osteotomy (3CO) for the correction of cervical deformity. METHODS A retrospective review was performed of patients who underwent a cervical or upper thoracic 3CO for cervical deformity correction by the senior author from 2008 to 2023. The main outcome of interest was DJF, defined as revision surgery with extension of the distal end of the fusion construct. Patients were excluded if the lowest instrumented vertebra (LIV) was the sacrum/pelvis, and if patients had prior autofusion throughout the distal part of the spine to the sacrum (e.g., ankylosing spondylitis). The minimum follow-up duration was 1 year. RESULTS One hundred fourteen patients were identified who underwent a cervical or upper thoracic 3CO for cervical deformity correction, 41 of whom met inclusion criteria for this study. The median patient age was 66 years, median BMI was 27, and 61% were male. Ten patients (24%) experienced DJF, requiring reoperation and distal extension of the construct to the pelvis in 9 cases and to L1 in 1 case. On univariable analysis, patients who experienced DJF compared with those who did not were more likely to be female (80% vs 35%, p = 0.007), had lower LIV Hounsfield units (HUs; 127 vs 167, p = 0.041), were less likely to have an LIV in a small autofused segment (10% vs 45%, p = 0.02), had an LIV that was closer to the first lordotic level (one level above vs three, p = 0.043), and had a longer length of fusion (17 vs 13 levels, p = 0.033). A stepwise multivariable regression model showed that having an LIV closer to the first lordotic vertebra was the only statistically significant predictor of DJF (OR 0.49, p = 0.013) and low LIV HUs did not reach statistical significance (OR 0.97, p = 0.09). CONCLUSIONS Patients with cervical deformity undergoing a 3CO are at higher risk for DJF with constructs terminating near the first lordotic vertebra. While LIV selection is complex and patient specific, choosing an LIV at least two levels above the first lordotic vertebra may help prevent DJF.