Multicenter expanded access program for access to investigational products for amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Expanded access (EA) is a Food and Drug Administration-regulated pathway to provide access to investigational products (IPs) to individuals with serious diseases who are ineligible for clinical trials. The aim of this report is to share the design and operations of a multicenter, multidrug EA program for amyotrophic lateral sclerosis (ALS) across nine US centers. METHODS: A central coordination center was established to design and conduct the program. Templated documents and processes were developed to streamline study design, regulatory submissions, and clinical operations across protocols. The program included three protocols and provided access to IPs that were being tested in respective regimens of the HEALEY ALS Platform Trial (verdiperstat, CNM-Au8, and pridopidine). Clinical and safety data were collected in all EA protocols (EAPs). The program cohorts comprised participants who were not eligible for the platform trial, including participants at advanced stages of disease progression and with long disease duration. RESULTS: A total of 85 participants were screened across the 3 EAPs from July 2021 to September 2022. The screen failure rate was 3.5%. Enrollment for the regimens of the platform trial was completed as planned and results informed the duration of the corresponding EAP. The verdiperstat EAP was concluded in December 2022. Mean duration of participation in the verdiperstat EAP was 5.8 ± 4.1 months. The CNM-Au8 and pridopidine EAPs are ongoing. DISCUSSION: Multicenter EAPs conducted in parallel to randomized clinical trials for ALS can successfully enroll participants who do not qualify for clinical trials.

Ultrasound-guided glenohumeral joint injections for shoulder pain in ALS: A case series.

Introduction: Shoulder pain is a common secondary impairment for people living with ALS (PALS). Decreased range of motion (ROM) from weakness can lead to shoulder pathology, which can result in debilitating pain. Shoulder pain may limit PALS from participating in activities of daily living and may have a negative impact on their quality of life. This case series explores the efficacy of glenohumeral joint injections for the management of shoulder pain due to adhesive capsulitis in PALS. Methods: People living with ALS and shoulder pain were referred to sports medicine-certified physiatrists for diagnostic evaluation and management. They completed the Revised ALS Functional Rating Scale and a questionnaire asking about their pain levels and how it impacts sleep, function, and quality of life at baseline pre-injection, 1-week post-injection, 1 month post-injection, and 3 months post-injection. Results: We present five cases of PALS who were diagnosed with adhesive capsulitis and underwent glenohumeral joint injections. Though only one PALS reported complete symptom resolution, all had at least partial symptomatic improvement during the observation period. No complications were observed. Conclusions: People living with ALS require a comprehensive plan to manage shoulder pain. Glenohumeral joint injections are safe and effective for adhesive capsulitis in PALS, but alone may not completely resolve shoulder pain. Additional therapies to improve ROM and reduce pain should be considered.

Ultrasound of the Median Nerve in the Surgical Treatment of Severe Carpal Tunnel Syndrome.

BACKGROUND: High-resolution ultrasound (HRU) has demonstrated utility in the diagnosis and treatment of carpal tunnel syndrome (CTS) by measuring the cross-sectional area (CSA) of the median nerve. We investigated whether HRU could be helpful in evaluating outcomes of carpal tunnel release in patients with severe CTS. METHODS: Patients greater than 18 years of age with severe CTS on electrodiagnostic (EDX) studies and scheduled to have carpal tunnel release were enrolled. At baseline visit within 6 weeks preoperatively, HRU was used to measure median nerve CSA at the carpal tunnel inlet and forearm, and the wrist/forearm ratio (WFR) was calculated. Patients also completed the Boston Carpal Tunnel Questionnaire (BCTQ). Ultrasound and BCTQ were repeated at 6 weeks and 6 months postoperatively. RESULTS: Twelve patients completed the study (average age, 69 years; range, 52-80 years). The WFR improved significantly at 6 weeks and reached normal levels at 6 months. The CSA at the wrist also improved at 6 months, although this did not reach statistical significance (P = .059). Boston Carpal Tunnel Questionnaire symptoms and function scores improved significantly at 6 weeks and 6 months. CONCLUSIONS: High-resolution ultrasound provides an objective assessment of surgical outcomes in cases of severe CTS, demonstrating normalization of WFR in our series of successful cases. Future study of poor outcomes may help determine whether improvement in WFR and CSA can provide reassurance and support for observation rather than reoperation. Ultrasound also provides anatomical evaluation and may be helpful in cases with medicolegal or psychosocial issues while potentially being less costly and better tolerated than EDX or magnetic resonance imaging.

High-Resolution Ultrasound in the Diagnosis and Surgical Management of Ulnar Neuropathy at the Elbow.

High-resolution ultrasound (HRU) has recently demonstrated the potential to facilitate diagnosis and treatment of upper extremity compression neuropathy. The authors hypothesized that HRU can improve preoperative evaluation of ulnar neuropathy at the elbow (UNE) and that changes in ulnar nerve cross-sectional area (CSA) after cubital tunnel release may correlate with outcomes. Nineteen adult patients diagnosed with UNE who were scheduled for surgical decompression by a single hand surgeon were enrolled. Electrodiagnostic (EDX) testing, HRU of the ulnar nerve, Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH) score, and McGowan grade were obtained pre- and postoperatively. Fourteen patients completed the study. Statistically significant improvements were found in CSA measurements and QuickDASH scores. High-resolution ultra-sound was found to confirm UNE in all 7 patients with positive results on EDX, and additionally detected UNE in 3 of 6 patients with negative results on EDX and in 1 patient with equivocal (nonlocalized) EDX testing. All 4 of these additional HRU-detected cases improved clinically and by CSA measurements after surgery. In this series, HRU was superior to EDX testing in the diagnosis of UNE and demonstrated objective improvement in ulnar nerve CSA after successful cubital tunnel release. This modality, which is better tolerated, less costly, and less time-consuming than EDX testing or magnetic resonance imaging, should therefore be considered in the diagnosis and surgical management of UNE, particularly in cases with negative or equivocal results on EDX testing, or when outcomes are suboptimal. [Orthopedics. 2021;44(5):285-288.].

Clinical Effects of the Self-administered Subcutaneous Complement Inhibitor Zilucoplan in Patients With Moderate to Severe Generalized Myasthenia Gravis: Results of a Phase 2 Randomized, Double-Blind, Placebo-Controlled, Multicenter Clinical Trial.

Importance: Many patients with generalized myasthenia gravis (gMG) have substantial clinical disability, persistent disease burden, and adverse effects attributable to chronic immunosuppression. Therefore, there is a significant need for targeted, well-tolerated therapies with the potential to improve disease control and enhance quality of life. Objective: To evaluate the clinical effects of zilucoplan, a subcutaneously (SC) self-administered macrocyclic peptide inhibitor of complement component 5, in a broad population of patients with moderate to severe gMG. Design, Setting, and Participants: This randomized, double-blind, placebo-controlled phase 2 clinical trial at 25 study sites across North America recruited participants between December 2017 and August 2018. Fifty-seven patients were screened, of whom 12 did not meet inclusion criteria and 1 was lost to follow-up after randomization but before receiving study drug, resulting in a total of 44 acetylcholine receptor autoantibody (AChR-Ab)-positive patients with gMG with baseline Quantitative Myasthenia Gravis (QMG) scores of at least 12, regardless of treatment history. Interventions: Patients were randomized 1:1:1 to a daily SC self-injection of placebo, 0.1-mg/kg zilucoplan, or 0.3-mg/kg zilucoplan for 12 weeks. Main Outcomes and Measures: The primary and key secondary end points were the change from baseline to week 12 in QMG and MG Activities of Daily Living scores, respectively. Significance testing was prespecified at a 1-sided α of .10. Safety and tolerability were also assessed. Results: The study of 44 patients was well balanced across the 3 treatment arms with respect to key demographic and disease-specific variables. The mean age of patients across all 3 treatment groups ranged from 45.5 to 54.6 years and most patients were white (average proportions across 3 treatment groups: 78.6%-86.7%). Clinically meaningful and statistically significant improvements in primary and key secondary efficacy end points were observed. Zilucoplan at a dose of 0.3 mg/kg SC daily resulted in a mean reduction from baseline of 6.0 points in the QMG score (placebo-corrected change, -2.8; P = .05) and 3.4 points in the MG Activities of Daily Living score (placebo-corrected change, -2.3; P = .04). Clinically meaningful and statistically significant improvements were also observed in other secondary end points, the MG Composite and MG Quality-of-Life scores. Outcomes for the 0.1-mg/kg SC daily dose were also statistically significant but slower in onset and less pronounced than with the 0.3-mg/kg dose. Rescue therapy (intravenous immunoglobulin or plasma exchange) was required in 3 of 15, 1 of 15, and 0 of 14 participants in the placebo, 0.1-mg/kg zilucoplan, and 0.3-mg/kg zilucoplan arms, respectively. Zilucoplan was observed to have a favorable safety and tolerability profile. Conclusions and Relevance: Zilucoplan yielded rapid, meaningful, and sustained improvements over 12 weeks in a broad population of patients with moderate to severe AChR-Ab-positive gMG. Near-complete complement inhibition appeared superior to submaximal inhibition. The observed safety and tolerability profile of zilucoplan was favorable. Trial Registration: ClinicalTrials.gov Identifier: NCT03315130.

Worsening of anti-Hu paraneoplastic neurological syndrome related to anti-PD-1 treatment: Case report and review of literature.

We present an illustrative case of a 62-year-old woman with small cell lung cancer who developed progressive worsening of pre-existing anti-Hu antibody associated sensory neuronopathy after treatment with programmed cell death-1 (PD-1) inhibitor, nivolumab. We review the literature and identify 6 reported cases to understand the clinical outcomes of patients with anti-Hu paraneoplastic neurologic syndrome (PNS) treated with anti-PD-1 treatment. The PNS clinical spectrum comprised of encephalitis, a combination of sensory neuronopathy and anti-NMDAR encephalitis, isolated sensory neuronopathy, and encephalomyelitis. Immune checkpoint inhibitor have the potential to worsen pre-existing anti-Hu PNS and may promote the development of anti-Hu PNS.

Spinal Epidural Venous Plexus Pathology in Hirayama Disease.

Hirayama disease is a rare juvenile amyotrophy that is often misdiagnosed as an unrelated, relentlessly progressive disease. We present the case of an 18-year-old man who presented with weakness and atrophy of the right forearm and hand. Dynamic cervical magnetic resonance imaging was used, revealing the classic findings of epidural venous plexus dilation and anterior displacement of the dural sac. In addition, dilation of the external vertebral venous plexus was visualized. We discuss the clinical utility of dynamic magnetic resonance imaging and the underlying pathophysiology of these findings in Hirayama disease.

A prospective study of benign fasciculation syndrome and anxiety.

INTRODUCTION: Benign fasciculations are common. Despite the favorable prognosis of benign fasciculation syndrome (BFS), patients are often anxious about their symptoms. In this study, we prospectively followed 35 patients with BFS over a 24-month period. METHODS: We conducted serial questionnaires to assess anxiety, associated symptoms, and duration. RESULTS: 71.4% of patients were men, and 34.4% were employed in the medical field. Most reported anxiety, but only 14% were anxious as measured by the Zung self-rating anxiety scale. Fasciculations were most common in the calves and persisted in 93% of patients. Anxiety levels did not change over time. Associated symptoms (subjective weakness, sensory symptoms, and cramps) were common and resolved to varying degrees. No patients developed motor neuron disease. DISCUSSION: BFS is a benign disorder that usually persists over time. Commonly associated symptoms include subjective weakness, sensory symptoms, and cramps. BFS is usually not associated with pathologic anxiety. Muscle Nerve 58:852-854, 2018.

Radiation-Induced Painful Neurogenic Hypertrophy Treated With Botulinum Toxin A.

Painful neurogenic hypertrophy is a rare complication of radiation therapy. We report a 27-year-old woman with a history of adenoid cystic carcinoma of the submandibular gland presented with painful twitching of her left shoulder. Electrodiagnostic studies were consistent with a diagnosis of radiation-induced spinal accessory nerve hyperactivity. The patient failed conventional medical therapy. She was treated with an injection of botulinum toxin A, and within 1 month experienced significant relief of symptoms. We thus conclude that Botulinum toxin is a therapeutic option for the pain associated with radiation-induced peripheral nerve hyperactivity.

Guillain-Barré syndrome incidence in a large United States cohort (2000-2009).

BACKGROUND/AIM: We describe the incidence of Guillain-Barré syndrome (GBS) in a large United States cohort. METHODS: Between 2000 and 2009, we identified visits with an ICD-9 code for GBS (357.0) from all persons with continuous enrollment for at least 1 year. The primary case definition was restricted to emergency department and inpatient visits. We calculated age-standardized rates and used multivariate Poisson regression to assess variation in rates by sex, age, season and year of diagnosis. We tabulated descriptive characteristics and the positive predictive value (PPV) for a subset of the visits with available medical record review. RESULTS: 1,619 visits with the GBS ICD-9 code were identified from 50,290,898 person-years of observation. After considering the PPV (55%) for record-reviewed visits, the age-standardized incidence rate was approximately 1.72/100,000 person-years. The rate was 40% higher for males and increased by 50% for every 10-year increase in age. The rate was 15% higher in winter and spring compared with summer. Rates were higher in more recent years. CONCLUSIONS: GBS rates are higher in males and increase considerably with age. The potential reasons for differences in rates by season and the increased rates in more recent years should be further investigated.

Risk of confirmed Guillain-Barre syndrome following receipt of monovalent inactivated influenza A (H1N1) and seasonal influenza vaccines in the Vaccine Safety Datalink Project, 2009-2010.

An increased risk of Guillain-Barré syndrome (GBS) following administration of the 1976 swine influenza vaccine led to a heightened focus on GBS when monovalent vaccines against a novel influenza A (H1N1) virus of swine origin were introduced in 2009. GBS cases following receipt of monovalent inactivated (MIV) and seasonal trivalent inactivated (TIV) influenza vaccines in the Vaccine Safety Datalink Project in 2009-2010 were identified in electronic data and confirmed by medical record review. Within 1-42 days following vaccination, 9 cases were confirmed in MIV recipients (1.48 million doses), and 8 cases were confirmed in TIV-only recipients who did not also receive MIV during 2009-2010 (1.72 million doses). Five cases following MIV and 1 case following TIV-only had an antecedent respiratory infection, a known GBS risk factor; furthermore, unlike TIV, MIV administration was concurrent with heightened influenza activity. In a self-controlled risk interval analysis comparing GBS onset within 1-42 days following MIV with GBS onset 43-127 days following MIV, the risk difference was 5.0 cases per million doses (95% confidence interval: 0.5, 9.5). No statistically significant increased GBS risk was found within 1-42 days following TIV-only vaccination versus 43-84 days following vaccination (risk difference = 1.1 cases per million doses, 95% confidence interval: -3.1, 5.4). Further evaluation to assess GBS risk following both vaccination and respiratory infection is warranted.

Rapid reversal of uremic neuropathy following renal transplantation in an adolescent.

Clinical and pathologic studies on adults with uremic neuropathy are numerous, but less is known about this disorder in children and adolescents. We report the clinical, electrophysiologic, and pathologic findings in an adolescent female with uremic neuropathy. Electrophysiologic findings were consistent with a primarily axonal sensorimotor polyneuropathy. Sural nerve biopsy revealed areas of focal depletion in myelin sheaths and loss of axons. Axonal degeneration with secondary myelin changes appears to be the characteristic pathology in this case, one of the youngest to our knowledge for which nerve biopsy data are available. Our patient experienced dramatic recovery after renal transplantation, similar to the reports of older patients.

Shoulder pain in amyotrophic lateral sclerosis.

OBJECTIVE: To determine the frequency of shoulder pain in our amyotrophic lateral sclerosis (ALS) population and to explore potential associations with demographic and clinical features. METHODS: We retrospectively reviewed the medical records of 193 patients with ALS patients seen at the Lahey Clinic between 2005 and 2009. Patients were categorized by the predominance of upper and lower motor neuron signs and the body regions initially involved. The frequency of shoulder pain was identified in each of these subgroups. RESULTS: Forty-five (23%) of the 193 patients reported shoulder pain at some time during the course of their illness. Age, gender, manual labor, prior shoulder problems, ALS phenotype, and initial region of involvement were not correlated with shoulder pain. Patients with shoulder pain were more likely to develop proximal arm weakness during their illness and to report pain elsewhere. CONCLUSIONS: Despite the limitations posed by this retrospective study, it underscores the prevalence of shoulder pain in patients with ALS. Further studies to identify risk factors, mechanisms of, and treatments for shoulder pain in patients with ALS may benefit this population.

Pain perception and nonsuicidal self-injury: a laboratory investigation.

People who engage in self-injurious behaviors such as cutting and burning may have altered pain perception. Using a community sample, we examined group differences in pain threshold and pain endurance between participants who self-injured and control participants who were exposed to pressure pain applied to the finger. Participants who self-injured had higher pain thresholds (time to report pain) and endured pain for longer than control participants. Among participants who self-injured, those with longer histories of self-injury had higher pain thresholds. Duration of self-injury was unrelated to pain endurance. Instead, greater pain endurance was predicted by higher levels of introversion and neuroticism and by more negative beliefs about one's self-worth. A highly self-critical cognitive style was the strongest predictor of prolonged pain endurance. People who self-injure may regard suffering and pain as something that they deserve. Our findings also have implications for understanding factors that might be involved in the development and maintenance of self-injury.

Influence of critical illness on axonal loss in Guillain-Barré syndrome.

In this study we sought to determine whether axonal damage in severe Guillain-Barré syndrome (GBS) was secondary to critical illness polyneuropathy (CIP) in the intensive care unit (ICU) by reviewing comorbidities in patients who had initial and follow-up electromyographic (EMG) studies. Patients were classified as demyelinating (EMG-D) or axonal (EMG-A) according to findings on the second EMG. A critical illness (CI) score, derived from components of the APACHE II score, assessed the severity of critical illness in the ICU. Forty-one patients were admitted to the ICU and had a follow-up EMG. Of these, 28 (68%) developed an EMG-A pattern. There was no difference in the timing of the second EMG (mean, 23 days) between the two groups. The mean CI score (10.7 for EMG-A vs. 9.2 for EMG-D, P = 0.47) and frequency of sepsis (89% vs. 77%, P = 0.36) were similar between the groups. Mean strength (0-100, Medical Research Council scale) and Hughes disability scores for the EMG-A group were significantly worse at admission, nadir, and discharge. EMG-A patients had significantly more days on the ventilator (25 vs. 11), in the ICU (26 vs. 15), and in the hospital (29 vs. 18). Sixty-eight percent of patients with GBS in the ICU developed axon loss, but this was not related to the usual precipitants of CIP.