The Miami Framework for ALS and related neurodegenerative disorders: an integrated view of phenotype and biology.

Increasing appreciation of the phenotypic and biological overlap between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, alongside evolving biomarker evidence for a pre-symptomatic stage of disease and observations that this stage of disease might not always be clinically silent, is challenging traditional views of these disorders. These advances have highlighted the need to adapt ingrained notions of these clinical syndromes to include both the full phenotypic continuum - from clinically silent, to prodromal, to clinically manifest - and the expanded phenotypic spectrum that includes ALS, frontotemporal dementia and some movement disorders. The updated clinical paradigms should also align with our understanding of the biology of these disorders, reflected in measurable biomarkers. The Miami Framework, emerging from discussions at the Second International Pre-Symptomatic ALS Workshop in Miami (February 2023; a full list of attendees and their affiliations appears in the Supplementary Information) proposes a classification system built on: first, three parallel phenotypic axes - motor neuron, frontotemporal and extrapyramidal - rather than the unitary approach of combining all phenotypic elements into a single clinical entity; and second, biomarkers that reflect different aspects of the underlying pathology and biology of neurodegeneration. This framework decouples clinical syndromes from biomarker evidence of disease and builds on experiences from other neurodegenerative diseases to offer a unified approach to specifying the pleiotropic clinical manifestations of disease and describing the trajectory of emergent biomarkers.

Causes of death among United States decedents with ALS: An eye toward delaying mortality.

OBJECTIVE: To report multiple cause of death (MCOD) occurrence among patients in the United States with amyotrophic lateral sclerosis (ALS). METHODS: Using death certificate data for all ALS deaths from 50 U.S. states and the District of Columbia, 2011-2014, we tabulated MCOD, used association rules mining (ARM) to determine if MCOD occurred together, and calculated standardized mortality odds ratios (SMOR) for select causes, comparing ALS with other U.S. decedents. RESULTS: Among 24,328 death certificates, there were 25,704 MCOD, excluding ALS. ALS was listed as the sole cause of death in n = 11,263 (46%). The most frequent causes of death co-occurring with ALS were respiratory failure (n = 6503; 25.3%), cardiovascular disease (n = 6077; 12.6%), pneumonia (n = 1345; 5.2%), and pneumonitis (n = 856; 3.3%). The SMORs among ALS decedents compared with non-ALS decedents for falls and accidents were 3.4 (95% CI 2.6, 4.3) and 3.0 (95% CI 2.2, 4.2), respectively. From ARM analysis, falls and accidents were both associated with injuries. The most common causes identified were weakly to very strongly associated with being an ALS decedent compared with other U.S. deaths, with SMOR point estimates ranging from 1.3 to 51.1. INTERPRETATION: This study provides information about the natural history of ALS. With knowledge that some causes of death may be preventable, healthcare providers may be able to optimize patient care and possibly postpone mortality and reduce morbidity. Moreover, this study located gaps in data; medical certifiers completing death certificates for ALS decedents should ensure all MCOD data are recorded.

Drug Cost-Effectiveness Assessments Require Standards for Rigor and Inclusion.

The Institute for Clinical and Economic Review (ICER), a nonprofit, nongovernmental organization, is the predominant independent price assessor in the United States. ICER's cost effectiveness assessments are increasingly being used to support health insurance coverage and healthcare policy decisions. ICER often does not apply rigorous data quality and inclusion criteria to either the assumptions embedded within their cost-effectiveness models or the data inputted into the models. Poor quality assumptions and data can lead to poor quality assessments. ICER should re-evaluate their reliance on quality adjusted life-years and equal value of life years gained as measures of drug effectiveness, establish data quality and inclusiveness minimum standards, produce cost-effectiveness assessments only when the minimum data is available, and prominently report data quality and inclusion limitations. These changes will increase the rigor and inclusiveness of drug price assessments and support sustainable access to high-value care for all Americans.

Understanding the needs of people with ALS: a national survey of patients and caregivers.

Objective: Amyotrophic lateral sclerosis (ALS) has profound effects on people with ALS (PALS) and caregivers. There is a paucity of research detailing and comparing PALS and caregiver day-to-day perspectives of ALS. Methods: A survey developed collaboratively by The ALS Association and a panel of experts in ALS care was designed to broadly sample the experience of PALS and caregivers with respect to physical and emotional symptoms, the efficacy of treatment approaches, and goals for future treatments. Specific physical symptoms assessed consisted of fatigue, pain, weakness, shortness of breath, difficulty sleeping, speech problems, depression and other mood changes, and cognitive changes. PALS, caregivers of living patients with ALS (C-LPALS), and caregivers of deceased patients with ALS (C-DPALS) were contacted by email to participate in a 30-minute online survey. Results: 887 PALS, 444 C-LPALS, and 193 C-DPALS responded to the survey. In comparison to PALS, C-LPALS perceived that PALS had significantly higher rates of all surveyed symptoms except for pain and weakness. Caregivers self-reported higher stress levels than PALS (p < 0.001). 35% (135/383) of caregivers reported experiencing a devastating or near devastating financial impact of ALS and 64% (247/383) of caregivers felt their own health had worsened. Caregivers were significantly less likely to perceive a positive response to treatment in comparison to PALS (p < 0.001). Conclusions: PALS and caregivers report a number of symptoms beyond weakness that affect daily life which may be targets of future interventions. There are opportunities to improve services and care for caregivers to reduce the burden of illness.

Arterial-spin labeling MRI identifies residual cerebral arteriovenous malformation following stereotactic radiosurgery treatment.

BACKGROUND AND PURPOSE: Brain arteriovenous malformation (AVM) treatment by stereotactic radiosurgery (SRS) is effective, but AVM obliteration following SRS may take two years or longer. MRI with arterial-spin labeling (ASL) may detect brain AVMs with high sensitivity. We determined whether brain MRI with ASL may accurately detect residual AVM following SRS treatment. MATERIALS AND METHODS: We performed a retrospective cohort study of patients who underwent brain AVM evaluation by DSA between June 2010 and June 2015. Inclusion criteria were: (1) AVM treatment by SRS, (2) follow-up MRI with ASL at least 30 months after SRS, (3) DSA within 3 months of the follow-up MRI with ASL, and (4) no intervening AVM treatment between the MRI and DSA. Four neuroradiologists blindly and independently reviewed follow-up MRIs. Primary outcome measure was residual AVM indicated by abnormal venous ASL signal. RESULTS: 15 patients (12 females, mean age 29 years) met inclusion criteria. There were three posterior fossa AVMs and 12 supratentorial AVMs. Spetzler-Martin (SM) Grades were: SM1 (8%), SM2 (33%), SM3 (17%), SM4 (25%), and SM5 (17%). DSA demonstrated residual AVM in 10 patients. The pooled sensitivity, specificity, positive predictive value, and negative predictive value of venous ASL signal for predicting residual AVM were 100% (95% CI: 0.9-1.0), 95% (95% CI: 0.7-1.0), 98% (95% CI: 0.9-1.0), and 100% (95% CI: 0.8-1.0), respectively. High inter-reader agreement as found by Fleiss' Kappa analysis (k = 0.92; 95% CI: 0.8-1.0; P < 0.0001). CONCLUSIONS: ASL is highly sensitive and specific in the detection of residual cerebral AVM following SRS treatment.

Evaluating Two Measures of Lumbar Spine MRI Overuse: Administrative Data Versus Chart Review.

PURPOSE: Lumbar spine (LS) MRI overuse may be identified in administrative data, but these data may lack the detailed clinical information needed to correctly assess overuse. The aim of this study was to compare chart review with analysis of administrative data to determine the appropriateness of LS MRI. METHODS: The sensitivity and specificity of the administrative method were determined, with inappropriateness regarded as the positive result, as if chart review determined the true state. Patients were the first 146 veterans who underwent LS MRI in the outpatient setting in fiscal year 2012 at the Veterans Affairs Palo Alto Health Care System. The InterQual criteria for chart review and the method of evaluating administrative data developed by CMS and endorsed by the National Quality Forum were used. Slight modifications were made to each measure to ensure completeness and comparability. RESULTS: Of the 146 scans reviewed, 23% were considered inappropriate by the administrative measure, whereas 59% were considered inappropriate by chart review. Compared with chart review, the administrative measure had specificity of 82% for identifying inappropriate scans and sensitivity of 27% for identifying appropriate scans. CONCLUSIONS: Compared with chart review, analysis of administrative data identified scans that were appropriate but underestimated inappropriate ordering. Contrary to expectations, chart review resulted in more scans being classified as inappropriate. The administrative method is economically feasible for identifying the overuse of LS MRI, but it underestimates the true extent of inappropriate ordering.

Findings and patterns on MRI and MR spectroscopy in neonates after therapeutic hypothermia for hypoxic ischemic encephalopathy treatment.

OBJECTIVES: The purpose of this study is to describe the findings and patterns of injury on magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) after whole-body hypothermia treatment for neonatal hypoxic ischemic encephalopathy. METHODS: A retrospective review of consecutive term neonates treated with whole-body hypothermia was performed. Data recorded included demographics and MRI and MRS findings, and day of life (DOL) studies were performed. Injury patterns were classified on MRI as deep, cortical, mixed, or diffuse. The relative apparent diffusion coefficient (rADC) was plotted against DOL scanned and the presence of lactate was recorded. RESULTS: MRI was performed in 44 infants, 34 of whom also underwent MRS. MRI was abnormal in 32% of neonates, 29.5% of whom were imaged at DOL 4 to 8. rADC values were lowest in neonates scanned on DOL 4 and 5 and remained low up to DOL 8. The deep brain nuclei were involved in hypoxic ischemic encephalopathy in 93% of neonates with abnormal MRIs and lactate was identified on MRS in 18% of neonates between DOL 4 and 8. CONCLUSIONS: MRI performed after therapeutic cooling was abnormal in 29.5% of neonates scanned on DOL 4 to 8. Deep nuclear injury was identified in 93% of neonates. Lactate was present on MRS in 18% of neonates, and rADC values were most reduced on MRI between DOL 4 and 8.

Borderline low conus medullaris on infant lumbar sonography: what is the clinical outcome and the role of neuroimaging follow-up?

BACKGROUND: Isolated borderline low conus medullaris is a frequent finding on screening lumbar sonography of unknown significance that often prompts further imaging and clinical follow-up. OBJECTIVE: To determine the clinical outcome and utility of follow-up neuroimaging in infants with isolated borderline low conus on lumbar sonography. MATERIALS AND METHODS: We reviewed 748 consecutive spinal sonograms identifying infants with conus terminating between L2-L3 disc space and mid-L3 level without other findings of tethered cord. We excluded infants with conditions associated with developmental delay and those who passed away, and compared the age of gross motor milestone achievement to normal ranges. Follow-up imaging was reviewed. RESULTS: Isolated borderline low conus was found in 90 of 748 infants (12%) on sonography. Seventy of those infants met inclusion criteria. Follow-up imaging in 11 children (10 MRI, 1 sonogram), showed change in conus position to "normal" level in 10, no change in 1, and no new findings within lumbar spine. Clinical follow-up was available in 50 of 70 (71%) children meeting inclusion criteria, with normal motor milestones met in all 50 children. CONCLUSION: Isolated borderline low conus is a common finding in infants who meet normal developmental milestones suggesting that follow-up evaluation has little utility and is likely unwarranted.

Cost shifting to jails after a change to managed mental health care.

OBJECTIVE: To determine whether managed mental health care for Medicaid enrollees in King County, Washington, has led to indirect cost-shifting to substitute treatments, such as jails and state mental hospitals that are free goods to providers. DATA SOURCES: Complete service records for 47,300 adults who used at least one of the following systems from 1993 to 1998: King County jail system, Medicaid, or the King County mental health system. Data were also obtained from the Washington State Hospital System. STUDY DESIGN: A quasi-experimental analysis that compares the difference in outcomes between the pre- and post-managed care periods for Medicaid enrollees compared to non-Medicaid enrollees. The outcomes-jail costs, state hospital costs, and county outpatient mental health costs-were estimated with two-part difference-in-differences models. The regressions control for person-level fixed effects on up to 66 months of data per person. DATA COLLECTION METHODS: Administrative data were collected from the jail, Medicaid, and mental health systems, then merged and cleaned. Additional data on costs were obtained in interviews. PRINCIPAL FINDINGS: There is a striking increase in the probability of jail use for persons on Medicaid following the introduction of managed care. There was a significant decrease in expenditures in the county mental health system for outpatient care. CONCLUSIONS: Managed care led to indirect cost-shifting, probably through poor access to services, which may have led to an increased probability of jail detention.

Integration of service systems for homeless persons with serious mental illness through the ACCESS program. Access to Community Care and Effective Services and Supports.

OBJECTIVE: The aim of this study was to evaluate the first of the two core questions around which the ACCESS (Access to Community Care and Effective Services and Supports) evaluation was designed: Does implementation of system-change strategies lead to better integration of service systems? METHODS: The study was part of the five-year federal ACCESS service demonstration program, which sought to enhance integration of service delivery systems for homeless persons with serious mental illness. Data were gathered from nine randomly selected experimental sites and nine comparison sites in 15 of the nation's largest cities on the degree to which each site implemented a set of systems integration strategies and the degree of systems integration that ensued among community agencies across five service sectors: mental health, substance abuse, primary care, housing, and social welfare and entitlement services. Integration was measured across all interorganizational relationships in the local service networks (overall systems integration) and across relationships involving only the primary ACCESS grantee organization (project-centered integration). RESULTS: Contrary to expectations, the nine experimental sites did not demonstrate significantly greater overall systems integration than the nine comparison sites. However, the experimental sites demonstrated better project-centered integration than the comparison sites. Moreover, more extensive implementation of strategies for system change was associated with higher levels of overall systems integration as well as project-centered integration at both the experimental sites and the comparison sites. CONCLUSIONS: The ACCESS demonstration was successful in terms of project-centered integration but not overall system integration.