Long-term safety and efficacy of zilucoplan in patients with generalized myasthenia gravis: interim analysis of the RAISE-XT open-label extension study.

Background: Generalized myasthenia gravis (gMG) is a chronic, unpredictable disease associated with high treatment and disease burdens, with a need for more effective and well-tolerated treatments. Objectives: To evaluate the long-term safety, tolerability, and efficacy of zilucoplan in a mild-to-severe, acetylcholine receptor autoantibody-positive (AChR+) gMG population. Design: Ongoing, multicenter, phase III open-label extension (OLE) study. Methods: Eligible patients had completed a qualifying randomized, placebo-controlled phase II or phase III zilucoplan study and received daily, self-administered subcutaneous 0.3 mg/kg zilucoplan. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Secondary efficacy endpoints included change from baseline in Myasthenia Gravis Activities of Daily Living (MG-ADL) score. Results: In total, 200 patients enrolled. At the cut-off date (8 September 2022), median (range) exposure to zilucoplan in RAISE-XT was 1.2 (0.11-4.45) years. Mean age at OLE baseline was 53.3 years. A total of 188 (94%) patients experienced a TEAE, with the most common being MG worsening (n = 52, 26%) and COVID-19 (n = 49, 25%). In patients who received zilucoplan 0.3 mg/kg in the parent study, further improvements in MG-ADL score continued through to Week 24 (least squares mean change [95% confidence interval] from double-blind baseline -6.06 [-7.09, -5.03]) and were sustained through to Week 60 (-6.04 [-7.21, -4.87]). In patients who switched from placebo in the parent study, rapid improvements in MG-ADL score were observed at the first week after switching to zilucoplan; further improvements were observed at Week 24, 12 weeks after switching (-6.46 [-8.19, -4.72]), and were sustained through to Week 60 (-6.51 [-8.37, -4.65]). Consistent results were observed in other efficacy endpoints. Conclusion: Zilucoplan demonstrated a favorable long-term safety profile, good tolerability, and sustained efficacy through to Week 60 with consistent benefits in a broad AChR+ gMG population. Additional long-term data will be available in future analyses. Trial registration: ClinicalTrials.gov identifier: NCT04225871 (https://clinicaltrials.gov/ct2/show/NCT04225871).

Non-dystrophic myotonia: 2-year clinical and patient reported outcomes.

INTRODUCTION/AIMS: Consistency of differences between non-dystrophic myotonias over time measured by standardized clinical/patient-reported outcomes is lacking. Evaluation of longitudinal data could establish clinically relevant endpoints for future research. METHODS: Data from prospective observational study of 95 definite/clinically suspected non-dystrophic myotonia participants (six sites in the United States, United Kingdom, and Canada) between March 2006 and March 2009 were analyzed. Outcomes included: standardized symptom interview/exam, Short Form-36, Individualized Neuromuscular Quality of Life (INQoL), electrophysiological short/prolonged exercise tests, manual muscle testing, quantitative grip strength, modified get-up-and-go test. Patterns were assigned as described by Fournier et al. Comparisons were restricted to confirmed sodium channelopathies (SCN4A, baseline, year 1, year 2: n = 34, 19, 13), chloride channelopathies (CLCN1, n = 32, 26, 18), and myotonic dystrophy type 2 (DM2, n = 9, 6, 2). RESULTS: Muscle stiffness was the most frequent symptom over time (54.7%-64.7%). Eyelid myotonia and paradoxical handgrip/eyelid myotonia were more frequent in SCN4A. Grip strength and combined manual muscle testing remained stable. Modified get-up-and-go showed less warm up in SCN4A but remained stable. Median post short exercise decrement was stable, except for SCN4A (baseline to year 2 decrement difference 16.6% [Q1, Q3: 9.5, 39.2]). Fournier patterns type 2 (CLCN1) and 1 (SCN4A) were most specific; 40.4% of participants had a change in pattern over time. INQoL showed higher impact for SCN4A and DM2 with scores stable over time. DISCUSSION: Symptom frequency and clinical outcome assessments were stable with defined variability in myotonia measures supporting trial designs like cross over or combined n-of-1 as important for rare disorders.

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.

Immunosuppressive and immunomodulatory therapies for neuromuscular diseases. Part II: New and novel agents.

While traditional immunosuppressive and immunomodulatory therapies remain the cornerstone of immune-mediated neuromuscular disease management, new and novel agents including antigen-specific, monoclonal antibody drugs, have emerged as important treatment options. This article is the second of a two-part series that reviews immune-based therapies in neuromuscular diseases. The first article provides an update on the use of traditional immune-based therapies such as corticosteroids, plasma exchange, steroid-sparing immunosuppressive drugs, and intravenous immunoglobulin G. This second article focuses on new and novel immune-based therapies, including eculizumab, a complement inhibitor approved for acetylcholine receptor antibody-positive myasthenia gravis; rituximab, a B-cell depletion therapy with evolving indications in neuromuscular diseases; and the subcutaneous formulation of immunoglobulin G that gained approval for use in chronic inflammatory demyelinating polyradiculoneuropathy in 2018. Finally, several novel antigen-specific drugs at different stages of investigation in neuromuscular disease are also reviewed.

Immunosuppressive and immunomodulatory therapies for neuromuscular diseases. Part I: Traditional agents.

Immunosuppressive and immunomodulatory therapies have had a major effect on the treatment of immune-mediated neuromuscular diseases. After the landmark introduction of synthetic corticosteroids, other therapies have become available, including plasma exchange (PLEX), immunoglobulin G (IgG), and steroid-sparing immunosuppressive drugs. More recently, novel biologically derived and antigen-specific pharmaceuticals have entered neuromuscular practice. Various levels of evidence guide the use of these treatments. This article reviews current immune-based therapies in neuromuscular diseases and is divided into two parts. Part I provides an update on the evidence and use of traditional therapies, such as corticosteroids, PLEX, intravenously delivered IgG (IVIG), and steroid-sparing immunosuppressive drugs. Part II focuses on the recently US Food and Drug Administration-approved therapies eculizumab and subcutaneous IgG (SCIG), the current indications for rituximab in neuromuscular disease, and on novel immunosuppressive therapeutic approaches under development.

Congenital Myasthenic Syndromes: a Clinical and Treatment Approach.

PURPOSE OF REVIEW: Congenital myasthenia syndromes are clinically and genetically heterogeneous but treatable conditions. Careful selection of drug therapy is paramount as the same drug can be effective, ineffective, and even harmful in different congenital myasthenia syndromes. The purpose of this article is to review current treatment options for these conditions. RECENT FINDINGS: Next-generation sequencing has accelerated the discovery of new genes and facilitated the description of novel congenital myasthenic syndromes. Retrospective therapy data from these newly identified syndromes has provided additional insight on the management of these conditions. Cholinergic agents, ß-adrenergic agonists, and open-channel blockers remain the principal treatment modalities, and their optimal use depends on an accurate genetic diagnosis and the timely clinical recognition of the disease. In particular, pyridostigmine, usually a first-line agent, should be avoided in DOK7, acetylcholinesterase deficiency, and slow-channel congenital myasthenic syndromes. Beta-adrenergic agonists have been recognized as a first-line agent for a number of congenital myasthenic syndromes, particularly DOK7 and acetylcholinesterase deficiency, whereas long-lived open-channel blockers of the acetylcholine receptor (AChR) ion channel are indicated for the slow-channel congenital myasthenic syndrome. Beta-adrenergic agonists additionally have an important adjunct treatment for congenital myasthenia syndrome due to glycosylation defects, fast channel syndrome, AChR deficiency, and choline acetyltransferase deficiency (ChaT) and therefore may be particularly important in the treatment of syndromes due to defects in motor endplate development and repair. Unlike in autoimmune myasthenia gravis, there is no role for immunotherapy in congenital myasthenic syndromes. If available, a genetic diagnosis should drive the choice for a first-line treatment agent between cholinergic agents, ß-adrenergic agents, and open-channel blockers. Evaluation and supportive care at centers with experience in these rare syndromes likely are paramount in achieving optimal outcomes. Furthermore, gene discovery for congenital myasthenic syndromes has provided novel insights on the role of protein glycosylation, endplate maintenance and repair, and synaptic vesicle exocytosis in neuromuscular transmission. These insights may lead to new therapeutic strategies in both congenital and autoimmune myasthenic diseases in the future.

Diagnosis of Myasthenia Gravis.

Myasthenia gravis (MG) diagnosis is primarily clinically based. By the end of the clinical evaluation, clinicians have a sense as to whether presenting symptoms and elicited signs are weakly or strongly supportive of MG. Diagnostic tests can reaffirm the clinicians' impression. Edrophonium testing is rarely used but helpful in cases of measurable ptosis. Decremental response on slow-frequency repetitive nerve stimulation has a modest diagnostic yield in ocular MG but is helpful in generalized MG cases. The most sensitive test is single-fiber electromyography. In this article, the authors review the diagnostic testing approach of practicing clinicians for suspected MG cases.

Treatment of Myasthenia Gravis.

With specialized care, patients with myasthenia gravis can have very good outcomes. The mainstays of treatment are acetylcholinesterase inhibitors, and immunosuppressive and immunomodulatory therapies. There is good evidence thymectomy is beneficial in thymomatous and nonthymomatous disease. Nearly all of the drugs used for MG are considered "off-label." The 2 exceptions are acetylcholinesterase inhibitors and complement inhibition with eculizumab, which was recently approved by the US Food and Drug Administration for myasthenia gravis. This article reviews the evidence base and provides a framework for the treatment of myasthenia gravis, highlighting recent additions to the literature.

Spontaneous Iliopsoas Tendon Rupture: An Uncommon Cause of Hip Pain in Elderly Patients.

Iliopsoas tendon rupture is a relatively rare cause of hip pain. It has been described in children, in adults with pathologic avulsion secondary to metastatic disease, and in older individuals with multiple chronic illnesses. We are reporting a case of apparently spontaneous iliopsoas tendon rupture that occurred in an elderly patient presenting with severe debilitating hip pain whose etiology initially was unrecognized. Magnetic resonance imaging of the hip confirmed the diagnosis. This case highlights the importance of considering iliopsoas tear in the differential diagnosis of unexplained acute onset hip pain and illustrates that geriatric patients with this condition can be treated conservatively with satisfactory functional outcome.

Acute headache diagnosis in pregnant women: a hospital-based study.

OBJECTIVE: To characterize demographic and clinical features in pregnant women presenting with acute headache, and to identify clinical features associated with secondary headache. METHODS: We conducted a 5-year, single-center, retrospective study of consecutive pregnant women presenting to acute care with headache receiving neurologic consultation. RESULTS: The 140 women had a mean age of 29 ± 6.4 years and often presented in the third trimester (56.4%). Diagnoses were divided into primary (65.0%) and secondary (35.0%) disorders. The most common primary headache disorder was migraine (91.2%) and secondary headache disorders were hypertensive disorders (51.0%). The groups were similar in demographics, gestational ages, and most headache features. In univariate analysis, secondary headaches were associated with a lack of headache history (36.7% vs 13.2%, p = 0.0012), seizures (12.2% vs 0.0%, p = 0.0015), elevated blood pressure (55.1% vs 8.8%, p < 0.0001), fever (8.2% vs 0.0%, p = 0.014), and an abnormal neurologic examination (34.7% vs 16.5%, p = 0.014). In multivariate logistic regression, elevated blood pressure (odds ratio [OR] 17.0, 95% confidence interval [CI] 4.2-56.0) and a lack of headache history (OR 4.9, 95% CI 1.7-14.5) had an increased association with secondary headache, while psychiatric comorbidity (OR 0.13, 95% CI 0.021-0.78) and phonophobia (OR 0.29, 95% CI 0.09-0.91) had a reduced association with secondary headache. CONCLUSIONS: Among pregnant women receiving inpatient neurologic consultation, more than one-third have secondary headache. Diagnostic vigilance should be heightened in the absence of a headache history and if seizures, hypertension, or fever are present. Attack features may not adequately distinguish primary vs secondary disorders, and low thresholds for neuroimaging and monitoring for preeclampsia are justified.

Headache and Pain in Guillain-Barré Syndrome.

While moderate and severe back or extremity pain is frequent in Guillain-Barré syndrome (GBS), headache appears to be uncommon. Most of the reports of headache in GBS place it in the context of the posterior reversible encephalopathy syndrome (PRES) which is increasingly recognized as a likely dysautonomia-related GBS complication. There are also a few reports of headache in the setting of increased CSF pressure and papilledema and in association with the Miller Fisher GBS variant. In comparison, back and extremity pain is highly prevalent. Aching muscle pain and neuropathic pain are the two most common of several pain types. Pain may be a heralding feature and has been described in patients as long as 2 years after disease onset. Pain management is a major axis of treatment in GBS. Gabapentin is a reasonable first-line choice, and opioid medications can be added for more severe pain but there are few clinical trials to inform specific recommendations. While the understanding of pain pathophysiology in GBS is incomplete, its prevalence and clinical impact are increasingly recognized and studied. Pain should be considered a cardinal manifestation of GBS along with acute, mostly symmetric weakness and diminished reflexes.

Cough syncope.

Loss of consciousness following cough was first described in 1876 as "laryngeal vertigo" Since then, several hundred cases of what is now most commonly termed cough syncope have been reported, often in association with various medical conditions. Some early authors assumed this entity to be a form of epilepsy, but by the mid-20th century, general consensus reflected that post-tussive syncope was a consequence of markedly elevated intrathoracic pressures induced by coughing. A typical profile of the cough syncope patient emerging from the literature is that of a middle-aged, large-framed or overweight male with obstructive airways disease. Presumably, such an individual would be more likely to generate the extremely high intrathoracic pressures associated with cough-induced fainting. The precise mechanism of cough syncope remains a matter of debate. Theories proposed include various consequences of the marked elevation of intrathoracic pressures induced by coughing: diminished cardiac output causing decreased systemic blood pressure and, consequently, cerebral hypoperfusion; increased cerebrospinal fluid (CSF) pressure causing increased extravascular pressure around cranial vessels, resulting in diminished brain perfusion; or, a cerebral concussion-like effect from a rapid rise in CSF pressure. More recent mechanistic studies suggest a neurally mediated reflex vasodepressor-bradycardia response to cough. Since loss of consciousness is a direct and immediate result of cough, elimination of cough will eliminate the resultant syncopal episodes. Thus, the approach to the patient with cough syncope requires thorough evaluation and treatment of potential underlying causes of cough, as summarized in several recently published cough management guidelines.

Coats syndrome in facioscapulohumeral dystrophy type 1: frequency and D4Z4 contraction size.

OBJECTIVE: To investigate the frequency of Coats syndrome and its association with D4Z4 contraction size in patients with facioscapulohumeral muscular dystrophy type 1 (FSHD1). METHODS: We searched a North American FSHD registry and the University of Rochester (UR) FSHD research database, reviewed the literature, and sent surveys to 14 FSHD referral centers in the United States and overseas to identify patients with genetically confirmed FSHD1 with a diagnosis of Coats syndrome. RESULTS: Out of 357 genetically confirmed patients in a North American FSHD registry and 51 patients in the UR database, 3 patients had a self-reported history of Coats disease (0.8%; 95% confidence interval 0.2%-2.2%). In total, we identified 14 patients with FSHD with known genetic contraction size and Coats syndrome confirmed by ophthalmologic examination: 10 from our survey and 4 from the literature. The median age at diagnosis of Coats syndrome was 10 years (interquartile range 14 years). The median D4Z4 fragment size was 13 kilobases (kb) (interquartile range 1 kb). One patient was mosaic (55% 11 kb, and 45% 78 kb). CONCLUSIONS: Coats syndrome is a rare extramuscular complication of FSHD1 associated with large D4Z4 contractions. Closer surveillance for retinal complications is warranted in patients with D4Z4 fragments ≤15 kb.

Regulatory subunit type I-alpha of protein kinase A (PRKAR1A): a tumor-suppressor gene for sporadic thyroid cancer.

The tumor-suppressor gene encoding the cyclic AMP-dependent protein kinase A type I-alpha regulatory subunit PRKAR1A has been mapped to chromosome 17 (17q22-24) and is mutated in Carney complex, a familial neoplasia syndrome that is associated with thyroid tumors. Other genes implicated in cyclic nucleotide-dependent signaling have been investigated in thyroid tumorigenesis. We studied protein kinase A (PKA) activity in noninherited follicular thyroid adenomas and follicular, papillary, and undifferentiated (anaplastic) thyroid carcinomas. We then examined these and additional thyroid tumors for losses of the 17q22-24 PRKAR1A region, mutations of the PRKAR1A gene, and expression of its peptide product. Total PKA activity was markedly increased in carcinomas over that in adenomas, whereas the ratio of free vs. total PKA activity was decreased in cancer. Consistent with these findings, the 17q22-24 region was frequently lost in cancer but not in benign adenomas. A novel inactivating mutation of the PRKAR1A gene (leading to premature termination of the predicted protein) was found in an aggressive thyroid cancer. The tumor with PRKAR1A gene mutation, as well as the tumors with 17q allelic losses, showed decreased PRKAR1A expression by immunostaining. We conclude that PRKAR1A, the most abundant regulatory subunit of protein kinase A and a principal cyclic AMP-signaling modulator, acts as a tumor-suppressor gene in sporadic thyroid cancer. Published 2002 Wiley-Liss, Inc.