HEAR-MHE study: Automated speech analysis identifies minimal hepatic encephalopathy and may predict future overt hepatic encephalopathy.

BACKGROUND AND AIMS: HE is a major cause of poor quality of life in patients with cirrhosis. A simple diagnostic test to identify minimal hepatic encephalopathy (MHE) and predict future overt HE (OHE) is lacking. We aimed to evaluate if analysis of speech patterns using a modern speech platform (1) correlates with validated HE tests, (2) correlates with MHE, and (3) predicts future OHE. APPROACH AND RESULTS: In a two-center prospective cohort study of 200 outpatients with cirrhosis and 50 controls, patients underwent baseline speech recording and validated HE diagnostic testing with psychometric HE score. Patients were followed for 6 months to identify episodes of OHE. Seven hundred fifty-two speech variables were extracted using an automated speech analysis platform, reflecting the acoustic, lexical, and semantic aspects of speech. Patients with cirrhosis were median 63 years old (IQR 54, 68), 49.5% (99) were female. Over 100 speech variables were significantly associated with psychometric HE score ( p <0.05 with false discovery rate adjustment). A three-variable speech model (2 acoustic, 1 speech tempo variable) was similar to animal naming test in predicting MHE (AUC 0.76 vs. 0.69; p =0.11). Adding age and MELD-Na improved the accuracy of the speech model (AUC: 0.82). A combined clinical-speech model ("HEAR-MHE model") predicted time to OHE with a concordance of 0.74 ( p =0.06). CONCLUSIONS: Automated speech analysis is highly correlated with validated HE tests, associated with MHE, and may predict future OHE. Future research is needed to validate this tool and to understand how it can be implemented in clinical practice.

Progressive multifocal leukoencephalopathy in dimethyl fumarate-treated multiple sclerosis patients.

Dimethyl fumarate (DMF), a fumaric acid with antioxidant and immunomodulatory properties, is among the most commonly used oral therapies for relapsing multiple sclerosis (MS). Progressive multifocal leukoencephalopathy (PML) has been associated with several disease-modifying therapies (DMTs), including DMF in treating MS. We present detailed clinical characteristics of nine PML cases and show that the PML incidence in DMF-treated patients is 0.02 per 1000 patients. In addition to persistent severe lymphopenia, older age appears to be a potential risk for PML. However, younger patients without lymphopenia were also observed to develop PML. DMF-associated PML has occurred in patients with absolute lymphocyte counts (ALCs) above the guideline threshold, suggesting that changes in specific subsets might be more important than total ALC. Furthermore, since DMF has been found to decrease immune cell migration by decreasing the expression of adhesive molecules, the cerebrospinal fluid (CSF) immune profile may also be useful for assessing PML risk in DMF-treated patients. This review provides an up-to-date assessment of PML cases occurring in DMF-treated patients and discusses other potential considerations in light of our current understanding of DMF's mechanism of action on the immune system in the periphery and in the central nervous system (CNS).

Reliability, construct validity and responsiveness to change of the PROMIS-29 in systemic sclerosis-associated interstitial lung disease.

OBJECTIVES: PROMIS-29 is a generic health-related quality of life instrument. Our objective was to assess the reliability, construct validity, and responsiveness to change of PROMIS-29 in systemic sclerosis-associated interstitial lung disease (SSc-ILD). METHODS: Seventy-three participants with SSc-ILD were administered patient reported outcomes (PROs) at baseline and follow-up visits which included PROMIS-29 and other measures of generic health, dyspnea, and cough instruments. We assessed internal consistency reliability using Cronbach's α, an alpha of ≥ 0.70 was considered satisfactory. We assessed the responsiveness to change using linear regression models. RESULTS: Mean age of the participants was 51.9 years and the mean disease duration was 7.9 years after first non-Raynaud's symptom. Of the 73 participants, 56.2% were classified as diffuse SSc and 26% limited SSc. The baseline (mean ± SD) FVC % predicted was 73.9±15.5 with a DLCO % predicted of 57.7±21.1; 95.9% had fibrotic NSIP pattern on HRCT. PROMIS-29 scores were 0.2 to 0.9 SD below the US population. Cronbach's α reliability was acceptable for all domains (ranged from 0.77 to 0.98). All scales showed statistically significant correlations with hypothesised PROMIS-29 domains (p≤0.05 for all comparisons). PROMIS-29 showed none-to-small discriminatory ability in comparison with physiologic measures (FVC and DLCO). There was no significant relationship between the change in FVC versus the change in PROMIS-29 measures over time. CONCLUSIONS: PROMIS-29 has adequate reliability and construct validity for evaluation in SSc-ILD. It has moderate-to-large correlations with other PROs. The PROMIS-29 domains were not found to change over time in this cohort, likely due to stable nature of the observational cohort.