Management of immune-mediated necrotizing myopathy.

The immune-mediated necrotizing myopathies (IMNM) are autoimmune myositides clinically characterized by proximal predominant weakness and elevated creatine kinase (CK). They may be associated with autoantibodies (anti-HMGCR, anti-SRP), triggered by statin use (e.g., anti-HMGCR myopathy), associated with cancer, or may be idiopathic. Immunotherapy is required to improve strength and decrease the CK level, but no therapies are currently approved by the U.S. Food and Drug Administration for the treatment of IMNM. The optimal treatment strategy for IMNM is currently unknown and wide practice variation exists in the management of this condition. However, observational studies and expert opinion suggest that certain therapies may be more effective for the different serological subtypes of IMNM. HMGCR IMNM often responds favorably to intravenous immunoglobulin (IVIG) even as monotherapy. Signal recognition peptide and seronegative IMNM typically require combination immunotherapy, most often consisting of an oral immunosuppressant, corticosteroids, and IVIG or rituximab. Patients often remain on immunotherapy for years and relapse is common during tapering of immunotherapy. Further studies are needed to guide the optimal management of these patients.

Migraine and the risk of cervical artery dissection: A systematic review and meta-analysis.

INTRODUCTION: Migraine is a common, disabling chronic pain condition possibly related to changes in endothelial and vascular structure and function. Several observational studies have suggested an elevated risk of cervical artery dissection (CeAD) in patients with a history of migraine. We aimed to investigate this potential association using systematic review and meta-analytic methods. PATIENTS AND METHODS: We utilized a pre-defined search protocol to identify and screen studies related to migraine and CeAD in PubMed, Embase, and the Web of Science Core Collection. We assessed the risk of bias and performed a meta-analysis of selected studies to assess the association between migraine and CeAD. We also performed subgroup analyses by migraine subtype, biological sex, and the use of stroke versus non-stroke controls. RESULTS: We identified 11 studies (N = 9857 patients) for inclusion in the meta-analysis. Meta-analysis showed an association between migraine and CeAD with an odds ratio of 1.74 (95%CI 1.38-2.19). There was high heterogeneity among the included studies (I2 = 61%). Publication bias was present but the Trim-Fill imputation suggested that the impact on results was likely minimal. Subgroup analyses revealed an association between migraine without aura and CeAD (OR 1.86, 95%CI 1.55-2.24) but not migraine with aura and CeAD (OR 1.15, 95%CI 0.71-1.88). There was no difference in the association between migraine and CeAD in men compared to women. DISCUSSION AND CONCLUSION: A history of migraine is associated with an increased risk of CeAD. Further studies are needed to elucidate the potential pathophysiologic mechanisms underlying this association.

Neuromuscular Complications of COVID-19: Evidence from the Third Year of the Global Pandemic.

Accumulating evidence in the third year of the global pandemic suggests that coronavirus disease 2019 (COVID-19) can cause neuromuscular complications during or after the acute phase of infection. Direct viral infection and immune-mediated mechanisms have been hypothesized. Furthermore, in patients with underlying autoimmune neuromuscular diseases, COVID-19 infection may trigger a disease flare. COVID-19 vaccines appear to be safe and effective at preventing severe illness from COVID-19. Certain vaccines are associated with an increased risk of Guillain-Barré syndrome and possibly Bell's palsy, but the absolute incidence is low, and benefits likely outweigh the risks. Newer prophylactic therapies and treatments are also becoming available for patients who may not mount a sufficient response to vaccination or have contraindications. In this article, we discuss the current available evidence on neuromuscular complications of COVID-19 and clinical considerations regarding vaccination.

Safety and outcomes of eculizumab for acetylcholine receptor-positive generalized myasthenia gravis in clinical practice.

INTRODUCTION/AIMS: Safety and outcomes data on eculizumab for generalized myasthenia gravis (gMG) in clinical practice remain limited. Outcomes and concomitant medication use may differ in practice compared with clinical trials. We analyzed the clinical and safety outcomes of patients who received eculizumab at our institutions. METHODS: Patients with acetylcholine receptor antibody positive (AChR+) gMG, who received ≥1 dose of eculizumab and had ≥1 follow-up before December 10, 2021, were identified. Data were abstracted by chart review. Outcomes included MG Foundation of America Post Intervention Status (MGFA-PIS), Clinical Classification (MGFA-CC), MG-Activities of Daily Living (MG-ADL), concurrent immunomodulatory therapy use, and adverse events. RESULTS: Twelve patients were included. Mean age at eculizumab initiation was 57.4 y (range, 21-77). Eight had refractory MG. Four had history of thymoma and thymectomy. A mean of 3.2 (range, 2-5) immunomodulatory therapies were previously tried. Mean follow-up duration was 18 mo (range, 2-21.6). Clinical improvement occurred rapidly; MGFA-PIS was improved in 80%, and MGFA-CC improved in 83% at 1 mo. Mean MG-ADL decreased from 8.7 to 2.8 at 1 mo, and remained ≤3 .5 over 1.5 y. Mean daily prednisone dose decreased from 22.5 mg to 7.2 mg at 1.5 y. Five of 7 patients discontinued maintenance IVIG or PLEX. No patients had meningococcal infections and adverse events were mild. DISCUSSION: Clinical improvement occurred in most patients after eculizumab initiation, beginning as quickly as 1 mo. Steroids were tapered and maintenance IVIG and PLEX were discontinued in most. Eculizumab had a favorable safety profile even when combined with other immunosuppressants.

Retrospective analysis of safety and outcomes of rituximab for myasthenia gravis in patients ≥65 years old.

INTRODUCTION/AIMS: Optimal management of myasthenia gravis (MG) in individuals ≥65 y old is unknown and patient factors may limit therapeutic choices. Safety and efficacy of rituximab in older patients with MG has not been well-studied. METHODS: This retrospective study examined 40 patients (14 patients ≥65 y old) treated with rituximab for MG. The primary efficacy outcome was the proportion of patients reaching "Improved" or better on Myasthenia Gravis Foundation of America (MGFA) Post-Intervention Status (PIS) at 12 mo, compared between younger and older patients. RESULTS: Ninety-two percent of patients ≥65 y old achieved MGFA PIS Improved or better at 12 mo compared to 69% of those <65 y old (P = .11). Median prednisone dose for the cohort decreased in the year following rituximab initiation (20 mg [interquartile range, 10-35] to 10 mg [0-13], P = .01). Non-refractory MG was predictive of favorable outcome, whereas age was not. Serious adverse events (SAEs) were similar between older and younger patients (21.4% vs. 30.8%, P = .715). No patients ≥65 y old required discontinuation of rituximab due to SAE. One death occurred in a patient <65 y old due to systemic inflammatory response syndrome. DISCUSSION: At 12 mo following initiation of rituximab for MG, patients ≥65 y old experienced similarly high rates of improvement in their myasthenic symptoms as younger patients, without an increased risk of experiencing SAEs. Rituximab should be considered in the treatment paradigm in older patients and in non-refractory MG patients of any age.

Skeletal Muscle and Peripheral Nerve Histopathology in COVID-19.

OBJECTIVE: To explore the spectrum of skeletal muscle and nerve pathology of patients who died after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and to assess for direct viral invasion of these tissues. METHODS: Psoas muscle and femoral nerve sampled from 35 consecutive autopsies of patients who died after SARS-CoV-2 infection and 10 SARS-CoV-2-negative controls were examined under light microscopy. Clinical and laboratory data were obtained by chart review. RESULTS: In SARS-CoV-2-positive patients, mean age at death was 67.8 years (range 43-96 years), and the duration of symptom onset to death ranged from 1 to 49 days. Four patients had neuromuscular symptoms. Peak creatine kinase was elevated in 74% (mean 959 U/L, range 29-8,413 U/L). Muscle showed type 2 atrophy in 32 patients, necrotizing myopathy in 9, and myositis in 7. Neuritis was seen in 9. Major histocompatibility complex-1 (MHC-1) expression was observed in all cases of necrotizing myopathy and myositis and in 8 additional patients. Abnormal expression of myxovirus resistance protein A (MxA) was present on capillaries in muscle in 9 patients and in nerve in 7 patients. SARS-CoV-2 immunohistochemistry was negative in muscle and nerve in all patients. In the 10 controls, muscle showed type 2 atrophy in all patients, necrotic muscle fibers in 1, MHC-1 expression in nonnecrotic/nonregenerating fibers in 3, MxA expression on capillaries in 2, and inflammatory cells in none, and nerves showed no inflammatory cells or MxA expression. CONCLUSIONS: Muscle and nerve tissue demonstrated inflammatory/immune-mediated damage likely related to release of cytokines. There was no evidence of direct SARS-CoV-2 invasion of these tissues. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that muscle and nerve biopsies document a variety of pathologic changes in patients dying of coronavirus disease 2019 (COVID-19).

Neuromuscular complications of coronavirus disease-19.

PURPOSE OF REVIEW: Since its outbreak in Wuhan, China in late 2019, coronavirus disease-19 (COVID-19) has become a global pandemic. The number of affected cases and deaths continues to rise. Primarily a respiratory illness, COVID-19 is now known to affect various organ systems including peripheral nerve and skeletal muscle. The purpose of this review is to discuss the scope of neuromuscular manifestations and complications of COVID-19. RECENT FINDINGS: Several neuromuscular conditions, including Guillain-Barré syndrome, rhabdomyolysis, and myositis, have been reported in patients infected with COVID-19, but even with a temporal association, a causal relationship remains unproven. Direct invasion of neurons or myocytes by the virus, and immune-mediated injury have been speculated but not consistently demonstrated. In addition to potentially causing the above conditions, COVID-19 can trigger exacerbations of preexisting neuromuscular conditions such as myasthenia gravis, and severe infections can lead to critical illness myopathy/polyneuropathy. SUMMARY: COVID-19 appears to be potentially associated with a wide range of neuromuscular manifestations and complications. Further studies are needed to examine these possible associations, understand the pathogenesis, and develop preventive and treatment strategies.

Pure White Cell Aplasia and Necrotizing Myositis.

Pure white cell aplasia (PWCA) is a rare hematologic disorder characterized by the absence of neutrophil lineages in the bone marrow with intact megakaryopoiesis and erythropoiesis. PWCA has been associated with autoimmune, drug-induced, and viral exposures. Here, we report a case of a 74-year-old female who presented with severe proximal weakness without pain and was found to have PWCA with nonspecific inflammatory necrotizing myositis and acute liver injury on biopsies. These findings were associated with a recent course of azithromycin and her daily use of a statin. Myositis improved on prednisone but PWCA persisted. With intravenous immunoglobulin and granulocyte-colony stimulating factor therapies, her symptoms and neutrophil counts improved and were sustained for months.

Lateralizing sensorimotor deficits in a case of pseudopheochromocytoma.

Pseudopheochromocytoma is a poorly understood, rare cause of severe paroxysmal hypertension that mimics the symptomatology of pheochromocytoma in the absence of biochemical evidence of this tumor. Symptoms such as headache, nausea, sweating, and palpitations during hypertensive episodes have been described. In this paper, we describe previously unreported findings of lateralizing sensorimotor deficits in a patient with pseudopheochromocytoma. These changes presented during a hypertensive episode and were concerning for stroke but were not accompanied by acute radiologic abnormalities. The deficits improved over 1.5 weeks as blood pressure stabilized with beta-blockade. We also review relevant literature on the clinical features, pathophysiology, and management of pseudopheochromocytoma.

Progressive increase in central nervous system immune activation in untreated primary HIV-1 infection.

BACKGROUND: Central nervous system (CNS) inflammation is a mediator of brain injury in HIV infection. To study the natural course of CNS inflammation in the early phase of infection, we analyzed longitudinal levels of soluble and cellular markers of inflammation in cerebrospinal fluid (CSF) and blood, beginning with primary HIV-1 infection (PHI). METHODS: Antiretroviral-naïve subjects identified as having PHI (less than one year since HIV transmission) participated in phlebotomy and lumbar puncture at baseline and at variable intervals thereafter. Mixed-effects models were used to analyze longitudinal levels of CSF neopterin and percentages of activated cluster of differentiation (CD)4+ and CD8+ T-cells (co-expressing CD38 and human leukocyte antigen-D-related (HLA-DR)) in blood and CSF. RESULTS: A total of 81 subjects were enrolled at an average of 100 days after HIV transmission and had an average follow-up period of 321 days, with the number of visits ranging from one to 13. At baseline, the majority of subjects had CSF neopterin concentrations above the upper limit of normal. The baseline concentration was associated with the longitudinal trajectory of CSF neopterin. In subjects with baseline levels of less than 21 nmol/L, a cutoff value obtained from a mixed-effects model, CSF neopterin increased by 2.9% per 10 weeks (n = 33; P <0.001), whereas it decreased by 6.7% in subjects with baseline levels of more than 21 nmol/L (n = 11; P = 0.001). In a subset with available flow cytometry data (n = 42), the percentages of activated CD4+ and CD8+ T-cells in CSF increased by 0.8 (P <0.001) and 0.73 (P = 0.02) per 10 weeks, respectively. CONCLUSIONS: Neopterin levels and the percentages of activated CD4+ and CD8+ T-cells in CSF progressively increase in most subjects without treatment during early HIV-1 infection, suggesting an accrual of intrathecal inflammation, a major contributor to neuropathology in HIV infection.

Clinical characteristics of refractory myasthenia gravis patients.

BACKGROUND: A subset of myasthenia gravis (MG) patients is refractory to standard therapies. Identifying the characteristics of this population is essential as newer treatment strategies emerge that may be more effective in this group. OBJECTIVE: The aim of our study is to describe the clinical features of refractory MG patients and compare them to those of non-refractory patients. METHODS: A retrospective chart review was completed of 128 MG patients referred to a tertiary neuromuscular clinic from 2003 to 2011. Patients were classified as refractory or non-refractory based on predefined criteria, and clinical features were compared. RESULTS: Nineteen out of 128 patients were classified as refractory (14.8 percent). Compared to the non-refractory patients, the refractory patients were more likely to be younger at onset, female, thymomatous, and MuSK-antibody positive. CONCLUSION: Refractory MG patients represent a small but distinct group for whom exploring newer therapeutic approaches and immunopathologic differences is warranted.