Sodium phenylbutyrate-taurursodiol access, adherence and adverse event in patients with amyotrophic lateral sclerosis: Experience at one center in the United States.

INTRODUCTION/AIMS: Sodium phenylbutyrate-taurursodiol (PB-TURSO) was recently approved for treating amyotrophic lateral sclerosis (ALS). Third-party payors' coverage policies are evolving, and adverse events are just being fully assessed. The goals of this study were to evaluate patients' experiences in obtaining and continuing PB-TURSO and assess adverse events and medication adherence. METHODS: Medical records of 109 ALS patients who were considered PB-TURSO candidates by the treating physician at a tertiary ALS clinic from October 2022 to May 2023 were reviewed. Data was recorded for demographics, clinical, and insurance information. A survey was e-mailed to patients asking about out-of-pocket expenses for PB-TURSO, financial assistance, medication start and (if applicable) stop dates, and reasons for discontinuation. RESULTS: Insurance information was available for 91 patients [57 males (62%); mean age 64.8 years (range 25.7-88)]. Of 79 who applied for insurance approval, 71 (90%) were approved; however, 19 required 1-3 appeals. Among 73 patients with available data about medication status, 54 started PB-TURSO and 19 did not, most commonly due to personal choice or out-of-pocket expenses. About 44% of patients (24/54) stopped taking PB-TURSO, primarily due to adverse events. Monthly out-of-pocket expenses varied from $0 to $3500 and 36 patients qualified for financial assistance. Administrative and nursing staff devoted 7.2 hours/week to the insurance authorization process. DISCUSSION: Most patients received insurance approval for PB-TURSO, but one-fourth required appeals. Some out-of-pocket costs were very high. Investment of staff time was substantial. These findings have implications for insurance coverage of, and adherence to, future ALS treatments.

Quality of life, cognitive and behavioural impairment in people with motor neuron disease: a systematic review.

PURPOSE: Motor neuron disease (MND) is a neurodegenerative disease, progressively impacting function and self-perceived quality of life (QoL). Up to 50% of people with MND can present with cognitive and behavioural impairment, with an associated increase in caregiver burden or strain. However, there has been no systematic exploration of the relationship between QoL and cognitive or behavioural impairment in MND. The aim was to determine if there is a relationship between QoL and cognitive/behavioural impairment in MND, while also supplementarily looking to determine the types of cognitive/behavioural and QoL measures utilised in these studies. METHODS: A systematic search was performed across multiple databases (PsychINFO, Embase, Medline, AMED) for research published up to the date of February 22, 2023. Studies utilising quantitative methods of measuring QoL, cognitive/behavioural functioning/impairment were included. Findings examining relationships between QoL-cognitive/behavioural impairment were extracted and synthesised. RESULTS: A total of 488 studies were identified, with 14 studies included in the systematic review. All 14 studies were observational (11 cross-sectional, 3 longitudinal). 13 studies utilised MND non-specific measures, particularly in relation to QoL and cognitive impairment. Of 8 studies measuring behavioural impairment 62.5% (N = 5) found either a lower QoL difference or association. Only 33.3% (N = 4) of 12 studies measuring cognitive impairment found a lower QoL difference or association. CONCLUSIONS: This systematic review shows that behavioural impairment may have an impact on QoL in MND. There is variability in types of assessments used to measure QoL and also cognitive/behavioural impairment, most of which are disease-non-specific. Recommendations for future research are to use comprehensive disease-specific, multidomain measures to further elucidate the QoL-cognitive/behavioural impairment relationship.

Ethical Perspectives on Treatment Options with Spinal Muscular Atrophy Patients.

Since 2016, 3 innovative therapies for spinal muscular atrophy (SMA) have changed the face of the disease. Although these therapies often result in remarkable improvements in infants and children, benefits in adults are modest and treatment is not curative. Concerns have been raised about the enormous costs of these medications, the ultimate burden to taxpayers, and the costs to society of withholding treatments and sacrificing or disadvantaging some individuals. Physicians are best positioned to serve our patients by carefully considering the costs, benefits, implications for quality of life (QOL), and the interplay of these factors within the framework of core ethical principles that guide clinical care. ANN NEUROL 2022;91:305-316.

Quality-of-life assessment instruments used across ALS clinics.

INTRODUCTION/AIMS: Instruments have been developed to assess quality of life (QoL) among people with amyotrophic lateral sclerosis (ALS). It is unclear whether these are utilized regularly in the clinical setting to guide individual patient care. In this study we aimed to understand the current use of instruments and existing barriers to assessing QoL in clinical ALS care. METHODS: An anonymous survey developed by Northeast ALS (NEALS) Consortium Palliative Committee members was distributed to all multidisciplinary NEALS members. Data were summarized via calculation of descriptive statistics. ALS Center characteristics were compared using chi-square and Fisher exact tests for categorical variables. RESULTS: Seventy-three (6.4%) of the 1132 NEALS members responded to the survey, representing 148 clinics, 49.3% of whom reported assessing QoL during clinic visits. The most used ALS-specific instruments were the ALS Assessment Questionnaire (19.4%) and Amyotrophic Lateral Sclerosis Specific Quality of Life scale (16.6%). Barriers reported were uncertainty regarding which instrument to use and length of visits. QoL assessment was not significantly correlated with length of clinic visit but with access to specialty palliative care. DISCUSSION: QoL assessments are performed by some, but not all, ALS centers during clinical visits. Although this study did have a low number of responding centers, the percentage, the proportion is similar to that seen in earlier studies, which limits the findings' generalizability. The value of QoL assessments' impact on outcomes should be further investigated and, if warranted, creative ways sought to increase the frequency of their use, including patient self-assessments before clinic and/or the use of teleheath to reduce the length of clinic visits.

Percutaneous endoscopic gastrostomy in amyotrophic lateral sclerosis: outcomes of a dedicated anesthesia and surgery protocol.

BACKGROUND: Patients requiring percutaneous endoscopic gastrostomy (PEG) for amyotrophic lateral sclerosis (ALS) related dysphagia represent a clinical challenge. Diminished pulmonary function and aspiration risks can lead to anesthesia-related complications, and gastric displacement from hemidiaphragm elevation may preclude safe gastric access. This study reports the efficacy and outcomes of a dedicated anesthesia/surgery management protocol for ALS patients undergoing PEG. METHODS: In 2013, a PEG placement protocol for ALS patients was developed emphasizing efficient pre-operative evaluation, rapidly metabolized anesthetic agents, and minimization of opioid use. Outcomes were analyzed retrospectively. Preoperative weight loss, pulmonary function tests, total analgesia, procedural time, and 90-day morbidity and mortality were recorded. RESULTS: From 2013-2019, 67 ALS patients (mean age 65.3 years, 52.2% female) received a PEG under the protocol. Mean percentage weight loss 6 months before PEG was 9.3 ± 5.1% with 38.8% of patients meeting criteria for severe malnutrition. Mean anesthesia time (propofol induction to anesthesia emergence) was 34.5 ± 10.8 min and mean operative time (endoscope insertion to dressing placement) was 16.4 ± 8.2 min. Regional anesthesia with liposomal bupivacaine was performed in 76.1%. All attempts at PEG placement were successful. With a mean follow-up of 6.1 ± 6.8 months, all PEGs were functional and there were no surgical site complications. Thirty-day readmission rate was 7.0% and 90-day mortality was 22.4% (46.7% occurring within 30 days). Mean time from surgery to death was 8.8 ± 7.8 months. CONCLUSIONS: Protocols for optimizing PEG may help overcome challenges present in the ALS patient population. Despite patient comorbidities, protocol implementation and dedicated team members resulted in a high procedural success rate and low complication rate. Further study is warranted to optimize the timing of PEG placement in relation to ALS disease progression and determine the utility of regional anesthesia during PEG placement.

Ten years of riluzole use in a tertiary ALS clinic.

INTRODUCTION/AIMS: Riluzole is a glutamate inhibitor approved for the treatment of amyotrophic lateral sclerosis (ALS). There are scant data on factors associated with riluzole initiation and adherence. The goal of this study was to describe the use of riluzole at the Penn State Hershey Medical Center (PSHMC) ALS clinic. METHODS: A retrospective medical record review of ALS patients seen at the PSHMC from January 2007 to December 2016. A timeline of riluzole use was established for each patient. Factors contributing to dose changes or discontinuations were recorded. Riluzole adherence was assessed using the proportion of days covered (PDC) calculated by the patient-reported length of riluzole use divided by total time from prescription to death/censor. Multivariable analysis was performed to evaluate the association of demography and clinical course with adherence. RESULTS: Seven hundred twenty-three records were screened, with 508 (307 men, 201 women) meeting the criteria for inclusion. The median duration of riluzole use was 435 (range, 0-3773) days. The median PDC for the group was 64%. Those with higher initial overall function and slower rate of decline were more likely to have a larger PDC. No trends in patients' demographics, riluzole use, and tracheostomy-free survival were found over time. DISCUSSION: A high rate of riluzole initiation and adherence was found in this sample. The most common reasons for dose modification were related to adverse effects, yet social-, economic-, and patient-related factors were also common. The characteristics of riluzole prescription and use have remained relatively unchanged in a single tertiary ALS center over the past 10 years.

Tocilizumab is safe and tolerable and reduces C-reactive protein concentrations in the plasma and cerebrospinal fluid of ALS patients.

INTRODUCTION/AIMS: We tested safety, tolerability, and target engagement of tocilizumab in amyotrophic lateral sclerosis (ALS) patients. METHODS: Twenty-two participants, whose peripheral blood mononuclear cell (PBMC) gene expression profile reflected high messenger ribonucleic acid (mRNA) expression of inflammatory markers, were randomized 2:1 to three tocilizumab or placebo treatments (weeks 0, 4, and 8; 8 mg/kg intravenous). Participants were followed every 4 wk in a double-blind fashion for 16 wk and assessed for safety, tolerability, plasma inflammatory markers, and clinical measures. Cerebrospinal fluid (CSF) was collected at baseline and after the third treatment. Participants were genotyped for Asp358 Ala polymorphism of the interleukin 6 receptor (IL-6R) gene. RESULTS: Baseline characteristics, safety, and tolerability were similar between treatment groups. One serious adverse event was reported in the placebo group; no deaths occurred. Mean plasma C-reactive protein (CRP) level decreased by 88% in the tocilizumab group and increased by 4% in the placebo group (-3.0-fold relative change, P < .001). CSF CRP reduction (-1.8-fold relative change, P = .01) was associated with IL-6R C allele count. No differences in PBMC gene expression or clinical measures were observed between groups. DISCUSSION: Tocilizumab treatment was safe and well tolerated. PBMC gene expression profile was inadequate as a predictive or pharmacodynamic biomarker. Treatment reduced CRP levels in plasma and CSF, with CSF effects potentially dependent on IL-6R Asp358 Ala genotype. IL-6 trans-signaling may mediate a distinct central nervous system response in individuals inheriting the IL-6R C allele. These results warrant further study in ALS patients where IL-6R genotype and CRP levels may be useful enrichment biomarkers.

Effects of mexiletine on hyperexcitability in sporadic amyotrophic lateral sclerosis: Preliminary findings from a small phase II randomized controlled trial.

BACKGROUND: To collect preliminary data on the effects of mexiletine on cortical and axonal hyperexcitability in sporadic amyotrophic lateral sclerosis (ALS) in a phase 2 double-blind randomized controlled trial. METHODS: Twenty ALS subjects were randomized to placebo and mexiletine 300 or 600 mg daily for 4 wk and assessed by transcranial magnetic stimulation and axonal excitability studies. The primary endpoint was change in resting motor threshold (RMT). RESULTS: RMT was unchanged with 4 wk of mexiletine (combined active therapies) as compared to placebo, which showed a significant increase (P = .039). Reductions of motor evoked potential (MEP) amplitude (P = .013) and accommodation half-time (P = .002), secondary outcome measures of cortical and axonal excitability, respectively, were also evident at 4 wk on mexiletine. CONCLUSIONS: The relative stabilization of RMT in the treated subjects was unexpected and could be attributed to unaccounted sources of error or chance. However, a possible alternative cause is neuromodulation preventing an increase. The change in MEP amplitude and accommodation half-time supports the reduction of cortical and axonal hyperexcitability with mexiletine.

Primary lateral sclerosis: consensus diagnostic criteria.

Primary lateral sclerosis (PLS) is a neurodegenerative disorder of the adult motor system. Characterised by a slowly progressive upper motor neuron syndrome, the diagnosis is clinical, after exclusion of structural, neurodegenerative and metabolic mimics. Differentiation of PLS from upper motor neuron-predominant forms of amyotrophic lateral sclerosis remains a significant challenge in the early symptomatic phase of both disorders, with ongoing debate as to whether they form a clinical and histopathological continuum. Current diagnostic criteria for PLS may be a barrier to therapeutic development, requiring long delays between symptom onset and formal diagnosis. While new technologies sensitive to both upper and lower motor neuron involvement may ultimately resolve controversies in the diagnosis of PLS, we present updated consensus diagnostic criteria with the aim of reducing diagnostic delay, optimising therapeutic trial design and catalysing the development of disease-modifying therapy.

Optimizing telemedicine to facilitate amyotrophic lateral sclerosis clinical trials.

Amyotrophic lateral sclerosis (ALS) has the largest drug pipeline among neuromuscular diseases, with over 160 companies actively involved in ALS research. There is a growing need to recruit trial participants, but ALS patients often have limited mobility and most ALS trials are conducted in a small number of major centers. These factors effectively limit patient participation, particularly for those in rural areas. The current coronavirus disease 2019 (COVID-19) pandemic has necessitated the more widespread use of telemedicine technology for clinical care, and has prompted consideration of its increased use for clinical trials. In this opinion piece, we describe the current state of telemedicine for recruitment, consenting, and screening of participants for clinical trials. We also summarize the available data on remote administration of outcome measures. Current challenges include validation of outcome measures for remote assessment, as well as technological, regulatory, and licensure barriers.

The Use of Telehealth to Enhance Care in ALS and other Neuromuscular Disorders.

Telehealth has the potential to improve the efficiency of healthcare while reducing the burden on patients and caregivers. Encounters can be synchronous or asynchronous. When used for care of those with amyotrophic lateral sclerosis (ALS) by individual health care providers or by a multidisciplinary team, synchronous telehealth is feasible, acceptable, may produce outcomes comparable to those of in-person care, and is cost effective. Individuals with ALS who use telehealth tend to have lower physical and respiratory function and to live farther from an ALS clinic than those who exclusively attend in-person clinic visits. Asynchronous telehealth can be used as a substitute full multidisciplinary visits, or for remote monitoring of pulmonary function, gait/falls, and speech. Barriers to implementing telehealth on a wider scale include disparities in access to technology and challenges surrounding medical licensure and billing, but these are being addressed.

COVID-19-associated Guillain-Barré syndrome: The early pandemic experience.

Guillain-Barré syndrome (GBS) is an inflammatory polyradiculoneuropathy associated with numerous viral infections. Recently, there have been many case reports describing the association between coronavirus disease-2019 (COVID-19) and GBS, but much remains unknown about the strength of the association and the features of GBS in this setting. We reviewed 37 published cases of GBS associated with COVID-19 to summarize this information for clinicians and to determine whether a specific clinical or electrodiagnostic (EDx) pattern is emerging. The mean age (59 years), gender (65% male), and COVID-19 features appeared to reflect those of hospitalized COVID-19 patients early in the pandemic. The mean time from COVID-19 symptoms to GBS symptoms was 11 days. The clinical presentation and severity of these GBS cases was similar to those with non-COVID-19 GBS. The EDx pattern was considered demyelinating in approximately half of the cases. Cerebrospinal fluid, when assessed, demonstrated albuminocytologic dissociation in 76% of patients and was negative for severe acute respiratory distress syndrome-coronavirus-2 (SARS-CoV-2) in all cases. Serum antiganglioside antibodies were absent in 15 of 17 patients tested. Most patients were treated with a single course of intravenous immunoglobulin, and improvement was noted within 8 weeks in most cases. GBS-associated COVID-19 appears to be an uncommon condition with similar clinical and EDx patterns to GBS before the pandemic. Future studies should compare patients with COVID-19-associated GBS to those with contemporaneous non-COVID-19 GBS and determine whether the incidence of GBS is elevated in those with COVID-19.

Amyotrophic lateral sclerosis care and research in the United States during the COVID-19 pandemic: Challenges and opportunities.

Coronavirus disease 2019 has created unprecedented challenges for amyotrophic lateral sclerosis (ALS) clinical care and research in the United States. Traditional evaluations for making an ALS diagnosis, measuring progression, and planning interventions rely on in-person visits that may now be unsafe or impossible. Evidence- and experience-based treatment options, such as multidisciplinary team care, feeding tubes, wheelchairs, home health, and hospice, have become more difficult to obtain and in some places are unavailable. In addition, the pandemic has impacted ALS clinical trials by impairing the ability to obtain measurements for trial eligibility, to monitor safety and efficacy outcomes, and to dispense study drug, as these also often rely on in-person visits. We review opportunities for overcoming some of these challenges through telemedicine and novel measurements. These can reoptimize ALS care and research in the current setting and during future events that may limit travel and face-to-face interactions.

Clinical features of LRP4/agrin-antibody-positive myasthenia gravis: A multicenter study.

INTRODUCTION: Our aim in this study was to identify the prevalence and clinical characteristics of LRP4/agrin-antibody-positive double-seronegative myasthenia gravis (DNMG). METHODS: DNMG patients at 16 sites in the United States were tested for LRP4 and agrin antibodies, and the clinical data were collected. RESULTS: Of 181 DNMG patients, 27 (14.9%) were positive for either low-density lipoprotein receptor-related protein 4 (LRP4) or agrin antibodies. Twenty-three DNMG patients (12.7%) were positive for both antibodies. More antibody-positive patients presented with generalized symptoms (69%) compared with antibody-negative patients (43%) (P ≤ .02). Antibody-positive patients' maximum classification on the Myasthenia Gravis Foundation of America (MGFA) scale was significantly higher than that for antibody-negative patients (P ≤ .005). Seventy percent of antibody-positive patients were classified as MGFA class III, IV, or V compared with 39% of antibody-negative patients. Most LRP4- and agrin-antibody-positive patients (24 of 27, 89%) developed generalized myathenia gravis (MG), but with standard MG treatment 81.5% (22 of 27) improved to MGFA class I or II during a mean follow-up of 11 years. DISCUSSION: Antibody-positive patients had more severe clinical disease than antibody-negative patients. Most DNMG patients responded to standard therapy regardless of antibody status.

Primary lateral sclerosis (PLS) functional rating scale: PLS-specific clinimetric scale.

INTRODUCTION: Our research aim was to develop a novel clinimetric scale sensitive enough to detect disease progression in primary lateral sclerosis (PLS). METHODS: A prototype of the PLS Functional Rating Scale (PLSFRS) was generated. Seventy-seven participants with PLS were enrolled and evaluated at 21 sites that comprised the PLSFRS study group. Participants were assessed using the PLSFRS, Neuro-Quality of Life (QoL), Schwab-England Activities of Daily Living (ADL), and the Clinical Global Impression of Change scales. Participants completed telephone assessments at 12, 24, and 48 weeks after enrollment. RESULTS: The PLSFRS demonstrated internal consistency as well as intrarater, interrater, telephone test-retest reliability, and construct validity. Significant changes in disease progression were detected at 6 and 12 months; changes measured by the PLSFRS vs the ALSFRS-R were significantly higher. DISCUSSION: The PLSFRS is a valid tool to assess the natural history of PLS in a shorter study period.

Do women's faces become more attractive near ovulation?

There have been mixed findings regarding whether raters judge women's natural faces more attractive when the women were photographed near ovulation relative to when photographed in other cycle regions. Bobst and Lobmaier (2012) isolated shape cues associated with ovulatory timing via computer morphing techniques and found that men judged face shapes characteristic of the fertile window as more attractive than those characteristic of the luteal phase. Here, we tested replication of their findings but also added stimuli from the early follicular phase. We constructed three composite faces constructed from photos of the same 23 women who had each been photographed in the early follicular phase, during the fertile window, and during the luteal phase. We next warped 20 other identity faces to the shapes of the composite faces representing each cycle phase, and asked male participants to rank order the resulting face triplets for attractiveness. Men ranked fertile window and luteal phase stimuli as more attractive than early follicular stimuli, but ranked fertile window and luteal phase faces as equally attractive. This result failed to replicate preferences for fertile window over luteal phase stimuli, and thereby argues against perceivers' ability to detect face shape cues of immediate fecundity. Because estradiol was lower in the early follicular phase relative to the other two cycle phases, our findings are consistent with the possibility that within-women increases in estradiol produce subtle increases in face shape attractiveness. Discussion addresses the overall evidence for facial cues of women's ovulatory timing.

ULTRASOUND IN THE DIAGNOSIS AND MONITORING OF AMYOTROPHIC LATERAL SCLEROSIS: A REVIEW.

Neuromuscular ultrasound is complementary to electrodiagnostic (EDx) testing and is useful in enhancing the diagnosis of mononeuropathies, peripheral nerve trauma, and demyelinating polyneuropathies. There is increasing interest in using ultrasound both to aid in the diagnosis of amyotrophic lateral sclerosis (ALS) and to monitor its progression. In this article we review the relevant literature on ultrasound in ALS. Ultrasound is more sensitive than EDx in identifying fasciculations in patients with ALS. It can detect decreased muscle thickness, increased muscle echointensity and echovariance, and reduced peripheral nerve size in these patients. Ultrasound is also a helpful tool in assessment of diaphragm function. Although additional studies are required to define the exact role of ultrasound in the evaluation and monitoring of ALS, it can improve the diagnostic yield in patients when ALS is suspected, but insufficiently supported, by clinical and EDx examinations. Muscle Nerve 60: 114-123, 2019.