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Introduction/aims: Riluzole improves survival in amyotrophic lateral sclerosis (ALS), but optimal time and duration of treatment are unknown. The aim of this study was to examine if timing of riluzole initiation and duration of treatment modified its effect on survival., Methods: Patients from the PRO-ACT dataset with information on ALS Functional Rating Scale, time from onset to enrollment (TFOE), and riluzole use were selected for analysis. Survival from enrollment was the outcome. Multivariable Cox proportional hazard models were examined for interactions between riluzole and TFOE. Inverse probability of treatment weighting (IPTW) was used to assess average treatment effect., Results: Of 4778 patients, 3446 (72.1%) had received riluzole. In unadjusted analyses, riluzole improved median survival significantly (22.6 vs. 20.2 months, log-rank p < 0.001). In multivariable analyses, no significant interaction between TFOE and riluzole was found. Riluzole effect was uniform during follow-up. By IPTW, estimated riluzole hazard ratio was 0.798 (95% confidence interval 0.686-0.927). Delaying riluzole initiation by 1 y (6 to 18 months from onset) may translate to reducing median survival from onset by 1.9 months (40.1 to 38.2 months)., Discussion: Riluzole appears to reduce risk of death uniformly, regardless of time from onset to treatment, and duration of treatment. Earlier treatment with riluzole may be associated with greater absolute survival gain from onset. Early diagnosis of ALS will facilitate early treatment and is expected to improve survival., (© 2022 The Authors. Muscle & Nerve published by Wiley Periodicals LLC.)

Objective : Examine sequence of weakness in arm muscles from longitudinal hand-held dynamometry (HHD) data in ALS for congruence with contiguous spread of neurodegeneration along spinal cord segments. Methods : Longitudinal HHD data from the Ceftriaxone clinical trial were examined using nonlinear mixed models, assuming a logistic trajectory from normal to zero strength. Unobserved baseline normal strength of weak muscles was assumed using strength of the best-preserved muscle. A novel metric called "time from onset to midway strength" (TOMS) was estimated for each muscle group, and TOMS ratios were examined to identify sequence of weakness, overall and by onset site. Results : Shoulder flexion (SF), elbow flexion (EF), elbow extension (EE), wrist extension (WE), and first dorsal interosseous (FDI) were measured on each side. Over a median of 36 weeks, 513 subjects provided 2589 sets of HHD measures. TOMS increased sequentially in the following order: FDI, WE, SF, EF, and EE. TOMS ratios estimates with 95% CIs (adjusted for multiple comparisons) were: WE/FDI 1.32 (1.24-1.41), SF/WE 1.06 (1.01-1.10), EF/SF 1.06 (1.02-1.10), and EE/EF 1.18 (1.12-1.23). Elbow and shoulder flexors weakened sooner than did elbow extensors. The sequence of arm muscle weakness progression was similar regardless of onset site. Conclusion : Nonsegmental progression of arm muscle weakness that is similar for different onset sites favors cortical influence/network spread over contiguous spread of neurodegeneration in the spinal cord. Furthermore, this study confirms the "split elbow" pattern. TOMS and other proposed methods may have value as outcome measures in clinical research.

Objectives: Reexamine cost-effectiveness of riluzole in the treatment of amyotrophic lateral sclerosis (ALS) in light of recent advances in disease staging and understanding of stage-specific drug effect., Methods: ALS was staged according to the "fine'til 9" (FT9) staging method. Stage-specific health utilities (EQ-5D, US valuation) were estimated from an institutional cohort, whereas literature informed costs and transition probabilities. Costs at 2018 prices were disaggregated into recurring costs (RCs) and "one-off" transition/"tollgate" costs (TCs). Five- and 10-year horizons starting in stage 1 disease were examined from healthcare sector and societal perspectives using Markov models to evaluate riluzole use, at a threshold of $100 000/quality-adjusted life year (QALY). Probabilistic and deterministic sensitivity analyses were conducted., Results: Mean EQ-5D utilities for stages 0 to 4 were 0.79, 0.74, 0.63, 0.54, and 0.46, respectively. From the healthcare sector perspective at the 5-year horizon, riluzole use contributed to 0.182 QALY gained at the cost difference of $12 348 ($5403 riluzole cost, $8870 RC and -$1925 TC differences), translating to an incremental cost-effectiveness ratio (ICER) of $67 658/QALY. Transition probability variation contributed considerably to ICER uncertainty (-30.2% to +90.0%). ICER was sensitive to drug price and RCs, whereas higher TCs modestly reduced ICER due to delayed tollgates., Conclusion: This study provides a framework for health economic studies of ALS treatments using FT9 staging. Prospective stage-specific and disaggregated cost measurement is warranted for accurate future cost-effectiveness analyses. Appropriate separation of TCs from RCs substantially mitigates the high burden of background cost of care on the ICER., (Copyright © 2020 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Purpose: Type 2 diabetes-related polyneuropathy (DPN) is associated with increased vascular events and mortality, but determinants and outcomes of pain in DPN are poorly understood. We sought to examine the effect of neuropathic pain on vascular events and mortality in patients without DPN, DPN with pain (DPN + P), and DPN without pain (DPN-P)., Methods: A retrospective cohort study was conducted within a large health system of adult patients with type 2 diabetes from January 1, 2009 through December 31, 2016. Using an electronic algorithm, patients were classified as no DPN, DPN + P, or DPN-P. Primary outcomes included number of vascular events and time to mortality. Independent associations with DPN + P were evaluated using multivariable negative binomial and Cox proportional hazards regression models, adjusting for demographics, socioeconomic characteristics, and comorbidities., Results: Of 43 945 patients with type 2 diabetes (age 64.6 ± 14.0 years; 52.1% female), 13 910 (31.7%) had DPN: 9104 DPN + P (65.4%) vs 4806 DPN-P (34.6%). Vascular events occurred in 4538 (15.1%) of no DPN patients, 2401 (26.4%) DPN + P, and 1006 (20.9%) DPN-P. After adjustment, DPN + P remained a significant predictor of number of vascular events (incidence rate ratio [IRR] = 1.55, 95% CI, 1.29-1.85), whereas no DPN was protective (IRR = 0.70, 95% CI, 0.60-0.82), as compared to DPN-P. Compared to DPN-P, DPN + P was also a significant predictor of mortality (hazard ratio = 1.42, 95% CI, 1.25-1.61)., Conclusions: Our study found a significant association between pain in DPN and an increased risk of vascular events and mortality. This observation warrants longitudinal study of the risk factors and natural history of pain in DPN., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives : To estimate the effect of riluzole on the stage-specific risk of progression of ALS. Methods : Patients from the PRO-ACT dataset were staged employing two methods (King's and FT9). Hazard ratios associated with riluzole treatment were estimated for forward transition between stages, using unadjusted and adjusted Markov multistate models. Results : Of 1903 patients, 1587 had received riluzole. Riluzole-treated patients survived non-significantly longer than those who did not (median 22.9 months vs. 18.3 months from time of initial observation, log rank p  = 0.16). After adjusting for age and ALSFRS-R slope at first visit, riluzole significantly reduced risk of the following transitions: (1) King's stages: 1->2 (hazard ratio (HR) = 0.81), and 2->3 (HR = 0.82), 4->death (HR = 0.57), and (2) FT9 stages: 1->2 (HR = 0.84), 3->4 (HR = 0.71), and 4->death (HR = 0.67). In contrast, the beneficial effect of riluzole in bulbar-onset patients was in early rather than late King's stages. Conclusions : This examination of cohorts closely followed in clinical trials finds a beneficial effect of riluzole that is predominantly but not exclusively in later stages of ALS. This analytic framework has utility to discern stage-specific treatment effects, and for refined health economic analyses.

Objective: We sought to examine prevalence and predictors of noninvasive ventilation (NIV) in a composite cohort of patients with amyotrophic lateral sclerosis (ALS) followed in a clinical trials setting (Pooled Resource Open-Access ALS Clinical Trials database)., Methods: NIV initiation and status were ascertained from response to question 12 of the revised ALS Functional Rating Scale (ALSFRS-R). Factors affecting NIV use in patients with forced vital capacity (FVC) ≤50% of predicted were examined. Predictors of NIV were evaluated by Cox proportional hazard models and generalized linear mixed models., Results: Among 1,784 patients with 8,417 simultaneous ALSFRS-R and FVC% measures, NIV was used by 604 (33.9%). Of 918 encounters when FVC% ≤50%, NIV was reported in 482 (52.5%). Independent predictors of NIV initiation were lower FVC% (hazard ratio [HR] 1.27, 95% confidence interval [CI] 1.17-1.37 for 10% drop), dyspnea (HR 2.62, 95% CI 1.87-3.69), orthopnea (HR 4.09, 95% CI 3.02-5.55), lower bulbar and gross motor subscores of ALSFRS-R (HRs 1.09 [95% CI 1.03-1.14] and 1.13 [95% CI 1.07-1.20], respectively, per point), and male sex (HR 1.73, 95% CI 1.31-2.28). Adjusted for other variables, bulbar onset did not significantly influence time to NIV (HR 0.72, 95% CI 0.47-1.08). Considerable unexplained variability in NIV use was found., Conclusion: NIV use was lower than expected in this ALS cohort that was likely to be optimally managed. Absence of respiratory symptoms and female sex may be barriers to NIV use. Prospective exploration of factors affecting adoption of NIV may help bridge this gap and improve care in ALS., (© 2019 American Academy of Neurology.)

Objectives: Propose an empirical amyotrophic lateral sclerosis (ALS) staging approach called Fine'til 9 (FT9) based on how many of the patient's ALS functional rating scale (ALSFRS-R) subscores are 9 or less (of normal 12). Gain insights into progression of ALS by applying Markov models to ALS stages by multiple systems (King's, Milan-Torino system (MITOS) and FT9)., Methods: Patients from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) dataset were staged using ALSFRS-R responses. Risks of progression through stages and death were estimated, as were effects of prognostic variables on these risks., Results: A total of 29,947 time points in 3199 patients from the PRO-ACT dataset were assigned stages. Although the three systems were moderately correlated, MITOS stages were heavily skewed toward advanced disease, whereas King's and FT9 stages were more balanced. Non-sequential progression was observed with King's system. Markov models adequately described transitions from stage to stage in the first year of observation, but underestimated risks beyond that point. Regardless of staging method, initial rate of ALSFRS-R decline had a powerful effect on rate of progression through sequential stages, whereas age predominantly influenced stage-specific mortality., Conclusion: King's and FT9 are more sensitive to observed progression of disease in clinical trials than MITOS. FT9 can partition the course similar to King's, and may have advantages of sequential progression and easy applicability to retrospective data. Markov transition intensity estimates may be of value for counseling, health economic studies, and research design. In particular, this framework permits estimation of multidimensional effects of variables (including treatment) on outcome.

Introduction: Rate of decline of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score is a common outcome measure and a powerful predictor of mortality in ALS., Methods: Observed rate of decline (postslope) of ALSFRS-R, its linearity, and its relationship to decline at first visit (preslope) were examined in the Pooled Resource Open-Access ALS Clinical Trials cohort by using longitudinal mixed effects models., Results: Mean ALSFRS-R postslope in 3,367 patients was -0.99 points/month. Preslope and postslope were correlated and had powerful effects on survival. ALSFRS-R trajectories were slightly accelerated overall, but slope and direction/degree of curvature varied. Subscore decline was sequential by site of onset. Respiratory subscore decline was the least steep., Discussion: Variable curvilinearity of ALSFRS-R trajectories confounds interpretation in clinical studies that assume linear decline. Subscore trajectories recapitulate phenotypic diversity and topographical progression of ALS. ALSFRS-R is better used as a multidimensional measure. Muscle Nerve 57: 937-945, 2018., (© 2017 Wiley Periodicals, Inc.)

Background: Pseudobulbar affect (PBA) is prevalent in amyotrophic lateral sclerosis (ALS), but there is limited information on its associations and course., Objectives: Explore prevalence, associations, course and manifestations of PBA in outpatient cohort of patients with ALS and examine its relationship to depression., Methods: Self-reported measures of PBA and depression (Center for Neurologic Study-Lability Scale (CNS-LS) and Patient Health Questionnaire (PHQ-9), respectively) were obtained from consecutive patients with ALS using tablet devices in waiting rooms (Knowledge Program)., Results: PBA (CNS-LS ≥13) was seen in 209/735 patients (28.4%). PBA was associated with bulbar onset and dysfunction, upper motor neuron dysfunction, cognitive impairment, depression and lower quality of life. A multivariable model that included lower bulbar and gross motor subscores, female gender, younger age and shorter duration of disease predicted PBA with 74% accuracy. CNS-LS scores increased only slowly with time. Women with PBA reported more crying than men. Crying (but not laughter) correlated with depression, and crying was associated with poorer quality of life. Exploratory factor analysis of pooled questions of CNS-LS and PHQ-9 identified three underlying factors (laughter, crying and depression) loaded on appropriate questions of the respective instruments., Conclusion: This study identifies associations of PBA and additionally finds PBA (especially crying-predominant PBA) more prevalent in women with ALS. Although the two self-report instruments (CNS-LS and PHQ-9) discriminate well between PBA and depression, there is significant overlap between depression and crying in PBA. Studies of PBA should stratify for gender, examine crying and laughter as separate outcomes and adjust for depression., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: To report an observational study of depression in a large cohort of patients with amyotrophic lateral sclerosis (ALS), including its prevalence, associations, longitudinal course, and effect on survival., Methods: The Patient Health Questionnaire-9 (PHQ-9) (a validated depression instrument) and other self-reported measures were obtained from patients with ALS as part of routine clinical care via tablet devices using a software system (Knowledge Program). Cox proportional hazard models, linear models, mixed effects models, and logistic regression were used for statistical analyses., Results: Of 1,067 patients seen over an 8-year period, 964 had at least one PHQ-9 recorded. Initially, at least moderate (PHQ-9 ≥ 10), moderately severe (PHQ-9 ≥ 15), and severe depression (PHQ-9 ≥ 20) were found in about 33%, 14%, and 5% of patients, respectively. Higher initial PHQ-9 was significantly predictive of mortality (hazard ratio 1.041 per increasing point, 95% confidence interval 1.018-1.065) after controlling for covariates. PHQ-9 was also associated with poorer quality of life. More advanced disease initially and pseudobulbar affect were associated with depression. In 587 patients with repeated PHQ-9 measures, worsening depression was not observed., Conclusion: Depression is prevalent in ALS and is associated with disease severity at initial assessment. Paradoxically, however, worsening depression is not observed during follow-up despite motor progression. Most importantly, depression has detrimental effects on survival and quality of life. Treatment of depression is recommended in ALS, although it is unknown if this would improve survival., (© 2016 American Academy of Neurology.)

Idiopathic intracranial hypertension (IIH) is a syndrome of unknown cause characterized by elevated intracranial pressure (ICP). While imaging often reveals a stenosis of the transverse sinuses, the role of this feature in IIH has been in dispute. Many patients with chronic daily headache have been found to actually be suffering from a milder form of IIH without papilledema (IIHWOP). These patients often demonstrate hypertensive B-waves and plateau-like waves upon continuous ICP monitoring. Recently, we presented modeling studies which suggest that the sinus stenosis and hypertension of IIH are physiological manifestations of a stable state of elevated pressures that exists when the transverse sinus is sufficiently collapsible. Many of the features of IIH were explained by this model but the prevalence of pathological ICP wave-forms observed in IIHWOP remained unresolved. The model presented here is a modified version of a previous model with a semi-collapsible sinus represented by a refined downstream Starling-like resistor based on experimental data. The qualitative behavior of this model is presented in terms of the collapsibility of the transverse sinus. For a sufficiently rigid sinus, there is a unique stable state of normal pressures. As the degree of collapsibility increases, there is a Hopf bifurcation, the normal state becomes unstable, low-frequency, high-amplitude ICP waves prevail, and small perturbations can lead to hypertensive ICP spikes. As the collapsibility increases further, so does the duration of the waves, until they are replaced by two stable states: one of normal pressures and one of elevated pressures. In this parameter domain, temporary perturbations can now cause permanent transitions between states. The model presented here retains the capability of our previous model to elucidate many features of IIH and additionally provides insight into the prevalence of the low-frequency, high-amplitude waves observed in IIHWOP.

Objective: To investigate the relationship between idiopathic intracranial hypertension (IIH) and transverse sinus stenosis through experiments performed on a validated mathematical model., Methods: A mathematical model of intracranial pressure (ICP) dynamics has been extended to accommodate venous sinus compression through the introduction of a Starling-like resistor between the sagittal and transverse sinuses., Results: In the absence of this type of resistor, the sinuses are rigid, and the model has only a unique, stable steady state with normal pressures. With resistance a function of the external pressure on the sinus, a second stable steady state may exist. This state is characterized by elevated ICP concurrent with a compressed transverse sinus. Simulations predict that a temporary perturbation that causes a transient elevation of ICP can induce a permanent transition from the normal to the higher steady state. Comparisons to clinical data from IIH patients provide supporting evidence for the validity of the model's predictions. Simulations suggest a possible clinical diagnostic technique to determine if an individual has a compressible transverse sinus and is at risk for developing IIH., Conclusions: Results of the model experiments suggest that the primary cause of IIH may be a compressible, as opposed to rigid, transverse sinus, and that the observed stenosis is a necessary characteristic of the elevated pressure state.

Idiopathic intracranial hypertension (IIH) is a syndrome of unknown etiology characterized by elevated intracranial pressure (ICP). Although a stenosis of the transverse sinus has been observed in many IIH patients, the role this feature plays in IIH is in dispute. In this paper, a lumped-parameter model is developed for the purpose of analytically investigating the elevated pressures associated with IIH and a collapsible transverse sinus. This analysis yields practical predictions regarding the degree of elevated ICPs and the effectiveness of various treatment methods. Results suggest that IIH may be caused by a sufficiently collapsible transverse sinus, but it is also possible that a stenosed sinus may persist following resolution of significant intracranial hypertension.

Background: Eye movements are clinically normal in most patients with motor neuron disorders until late in the disease course. Rare patients are reported to show slow vertical saccades, impaired smooth pursuit, and gaze-evoked nystagmus. We report clinical and oculomotor findings in three patients with motor neuronopathy and downbeat nystagmus, a classic sign of vestibulocerebellar disease., Case Presentation: All patients had clinical and electrodiagnostic features of anterior horn cell disease. Involvement of finger and wrist extensors predominated, causing finger and wrist drop. Bulbar or respiratory dysfunction did not occur. All three had clinically evident downbeat nystagmus worse on lateral and downgaze, confirmed on eye movement recordings using the magnetic search coil technique in two patients. Additional oculomotor findings included alternating skew deviation and intermittent horizontal saccadic oscillations, in one patient each. One patient had mild cerebellar atrophy, while the other two had no cerebellar or brainstem abnormality on neuroimaging. The disorder is slowly progressive, with survival up to 30 years from the time of onset., Conclusion: The combination of motor neuronopathy, characterized by early and prominent wrist and finger extensor weakness, and downbeat nystagmus with or without other cerebellar eye movement abnormalities may represent a novel motor neuron syndrome.