Vision Loss as a Presenting Feature of Chronic Inflammatory Demyelinating Polyneuropathy: A Case Series.

BACKGROUND: Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired, immune-mediated, and clinically heterogeneous demyelinating disease affecting the nerve roots and peripheral nerves. We report a series of 4 patients who presented with early and progressive vision loss in the context of new-onset CIDP: 3 due to papilledema and 1 due to optic neuropathy without papilledema. METHODS: This was a retrospective case series of 4 patients with vision loss as a presenting feature of CIDP evaluated at the Hospital of the University of Pennsylvania from January 2016 to August 2021. Demographic, clinical, diagnostic, and treatment data were collected via retrospective medical record review. RESULTS: Case 1 was a 51-year-old man with 2 months of progressive bilateral papilledema associated with reduced visual acuity (count fingers at 1 foot in each eye) and severely constricted visual fields. Case 2 was a 36-year-old man with 4 months of worsening headaches, reduced visual acuity (count fingers at 1 foot in each eye), severely constricted visual fields, and papilledema. Case 3 was a 39-year-old man with papilledema causing progressive vision loss (20/80 in both eyes), headaches, and relapsing limb sensorimotor deficits. Case 4 was a 19-year-old man with 3 months of progressive bilateral visual decline (20/400 in the right eye, 20/600 in the left eye), central scotoma, and optic disc pallor consistent with optic neuropathy without papilledema. All 4 patients met clinical and electrodiagnostic criteria of CIDP. Cases 3 and 4 each tested positive for serum neurofascin-155 IgG4 antibodies. All patients were managed with immunomodulatory therapy. Cases 1 and 2 also each required surgical intervention with bilateral optic nerve sheath fenestration and cerebrospinal fluid (CSF) shunting procedures. CONCLUSION: Vision loss from optic neuropathy with or without papilledema has rarely been reported in CIDP, and typically has been described in the context of longstanding disease. Our cases highlight how CIDP can present with early vision loss that may be profound and challenging to manage if diagnosis is delayed. CIDP should be considered in any patient with new progressive vision loss when associated with peripheral sensorimotor symptoms and elevated CSF protein. The small subgroup of CIDP patients with neurofascin-155 antibodies may be at particular risk of optic nerve involvement.

Pharmacosafety of fluoroquinolone and macrolide antibiotics in the clinical care of patients with myasthenia gravis.

INTRODUCTION/AIMS: Anecdotal case reports have suggested a potential association of fluoroquinolones and macrolides with myasthenia gravis (MG) exacerbation, prompting warnings against the use of these drugs in this population. However, large-scale and reliable population-based data that demonstrate this association are lacking. This study aims to examine the association between outpatient treatment with fluoroquinolones or macrolides and MG-related hospitalization. METHODS: A retrospective cohort study consisting of adult MG patients was conducted using a large de-identified healthcare claims database. Antibiotic prescription claims were identified, and MG-related hospitalizations were assessed at 15, 30, and 90 days after the date of prescription. We used mixed effects survival regression with log-logistic distribution and independent covariance matrix to estimate odds ratios (ORs) of hospitalization for each potentially exacerbating antibiotic using beta-lactam as the reference and adjusting for covariates. RESULTS: Among 1556 MG patients receiving 894 fluoroquinolone prescriptions, 729 macrolide prescriptions, and 1608 beta-lactam prescriptions during the study period, there was no difference in 15, 30, or 90-day odds of MG-related hospitalization between fluoroquinolone or macrolide users compared to prescribed beta-lactams. However, estimates were higher for fluoroquinolones than macrolides, even after covariate adjustment (adjusted OR [aOR] 4.60, 95% confidence interval [CI] 0.55-38.57 for fluoroquinolones and OR 0.56, 95% CI 0.32-0.97 for macrolides, respectively, at 15 days). DISCUSSION: Fluoroquinolone and macrolide antibiotics are prescribed frequently to patients with MG. While statistical imprecision precludes a definitive conclusion, elevated ORs for fluoroquinolones raise the possibility of an underpowered association that merits further investigation.

Acute Manifestations of Neuromuscular Disease.

Neuromuscular emergencies may be defined as disorders or exacerbation of diseases of the peripheral nervous system that are rapidly progressive and potentially life-threatening. Such disorders can affect any level of the peripheral nervous system, from the muscle to the anterior horn cell. While their clinical manifestations may vary, severe morbidity and mortality is most frequently the result of neuromuscular respiratory failure. Some disorders, such as Guillain-Barré syndrome, provide the additional threat of severe, and potentially irreversible, nerve loss. Others, such as rhabdomyolysis and malignant hyperthermia, may produce serious medical complications. This article reviews neuromuscular emergencies by localization in the peripheral nervous system of the underlying disorder, as well as the identification and management of neuromuscular respiratory failure.

Trends and Disparities in the Utilization of Thymectomy for Myasthenia Gravis in the United States.

Background and Objectives: In 2016, a randomized controlled trial demonstrated the clinical efficacy of trans-sternal thymectomy for patients with non-thymomatous myasthenia gravis (MG). Whether large-scale changes occurred in clinical practice after this trial is unknown. Methods: We performed a retrospective longitudinal cross-sectional analysis using National Inpatient Sample (NIS) data from 2012 to 2019. Our study included hospitalized adults at least 18 years of age diagnosed with MG without an associated thymoma. We used joinpoint regression to analyze annual trends in thymectomy volume and surgical approach (minimally invasive vs trans-sternal) from 2012 to 2019. Using logistic regression models, we examined patient and hospital-level factors that may have influenced whether thymectomy was performed, such as age, sex, race, insurance payor, hospital size and teaching status, and Elixhauser Comorbidity Index. Sampling weights were applied to account for the complex survey design of NIS. Results: The total number of thymectomy procedures increased by 69.8% per year (95% CI 40.1-105.8) between 2012 and 2019. Trans-sternal thymectomies increased by 62.8% per year (95% CI 35.8-95.2) and minimally invasive thymectomies by 83.7% per year (95% CI 38.1-144.3). Thymectomies were significantly more likely to occur in 2017-2019 compared with 2012-2016 (OR 1.93, 95% CI 1.62-2.31). In a multivariable regression model, several factors decreased the odds of patients with MG having a thymectomy: older age, Black race (OR 0.62, 95% CI 0.49-0.77), female (OR 0.73, 95% CI 0.63-0.86), and higher Elixhauser Comorbidity Index. Patients in medium (OR 1.82, 95% CI 1.30-2.55) or large (OR 2.81, 95% CI 2.07-3.82) size and urban teaching hospitals (OR 6.09, 95% CI 2.65-13.97) were more likely to undergo thymectomy. Discussion: Thymectomy is being performed more frequently for non-thymomatous MG, especially after 2016 after publication of a positive phase III clinical trial. There are several disparities in thymectomy utilization that warrant further attention.

Myopathy associated BAG3 mutations lead to protein aggregation by stalling Hsp70 networks.

BAG3 is a multi-domain hub that connects two classes of chaperones, small heat shock proteins (sHSPs) via two isoleucine-proline-valine (IPV) motifs and Hsp70 via a BAG domain. Mutations in either the IPV or BAG domain of BAG3 cause a dominant form of myopathy, characterized by protein aggregation in both skeletal and cardiac muscle tissues. Surprisingly, for both disease mutants, impaired chaperone binding is not sufficient to explain disease phenotypes. Recombinant mutants are correctly folded, show unaffected Hsp70 binding but are impaired in stimulating Hsp70-dependent client processing. As a consequence, the mutant BAG3 proteins become the node for a dominant gain of function causing aggregation of itself, Hsp70, Hsp70 clients and tiered interactors within the BAG3 interactome. Importantly, genetic and pharmaceutical interference with Hsp70 binding completely reverses stress-induced protein aggregation for both BAG3 mutations. Thus, the gain of function effects of BAG3 mutants act as Achilles heel of the HSP70 machinery.

Natural progression of diabetic peripheral neuropathy in the Zenarestat study population.

OBJECTIVE: The aim of this study was to report the baseline and natural progression of diabetic peripheral neuropathy over 12 months in a large mild-to-moderate neuropathy population. RESEARCH DESIGN AND METHODS: Patients from a multicentered trial of zenarestat, an aldose reductase inhibitor, had serial measures of neurologic function, including nerve conduction studies (NCSs), quantitative sensory testing (QST), and clinical neuropathy rating scores at baseline and at 12 months. Baseline population descriptors and changes in neurologic function in placebo-treated patients were analyzed. RESULTS: Sural sensory velocity (P = 0.0008 [95% CI -1.04 to -0.27]), median sensory amplitude (P = 0.0021 [-1.3 to -0.29]), median distal motor latency (P = 0.002 [0.09-0.28]), cool thermal QST (P = 0.0005 [0.27-0.94]), and Michigan Neuropathy Screening Instrument results (P = 0.0087 [0.04-0.30]) declined significantly from baseline in the placebo population. NCS changes from baseline were independent of baseline HbA1c stratification. CONCLUSIONS: The neurologic decline over 12 months is evident when measured by NCS and cool thermal QST. Other measures (vibration QST, neuropathy rating scores, monofilament examination) are insensitive to changes over 12 months in a mild-to-moderate affected population of this size.

Transcervical thymectomy for myasthenia gravis achieves results comparable to thymectomy by sternotomy.

BACKGROUND: It remains controversial whether transcervical thymectomy offers results equivalent to thymectomy by way of a median sternotomy in the treatment of myasthenia gravis. Furthermore, preoperative prognostic factors have not been clearly defined. METHODS: This study is a retrospective chart review and interview of 78 patients completing transcervical thymectomy for myasthenia gravis between 1992 and 1999. RESULTS: There were 24 men and 54 women. Mean age was 40 years (range, 13 to 78 years). Twelve patients were in Osserman class 1, 25 in class 2, 30 in class 3, and 11 in class 4 (mean, 2.5). There was no perioperative mortality and 6 (7.7%) morbidities. Mean length of stay was 1.5 days and mean follow-up, 54.6 months. The crude cumulative complete remission (asymptomatic off medications for 6 months) rate was 39.7% (n = 31). Only 8 patients (10.3%) failed to improve after transcervical thymectomy. Kaplan-Meier estimates of complete remission were 31% and 43% at 2 and 5 years, respectively. Eight patients with thymoma had a 5-year estimated complete remission rate of 75% in contrast to 43% in 38 patients with thymic hyperplasia and 36% in 32 patients with neither thymoma nor hyperplasia (p = 0.01). Twelve patients with ocular myasthenia had a 5-year estimated complete remission rate of 57%, whereas patients with mild-to-moderate (n = 55) or severe (n = 11) generalized symptoms had 5-year complete remission rates of 43% and 30%, respectively (p = 0.21). CONCLUSIONS: Overall, extended transcervical thymectomy offers results that are comparable to those published for the transsternal procedure. Patients with milder disease (including isolated ocular disease) and taking no preoperative immunosuppressive agents appear to experience higher remission rates. In contrast to previous studies, we also find that small thymomas predict better responses to thymectomy.

Myasthenia gravis with presynaptic electrophysiologic abnormalities.

OBJECTIVES: To describe the clinical, serologic, and electrophysiologic features of 2 patients with myasthenia gravis (MG), who also had presynaptic electrophysiologic abnormalities. METHODS: Case reports. RESULTS: Two patients developed clinical symptoms consistent with MG. They lacked autonomic symptoms or signs, and their reflexes were not absent. Acetylcholine receptor antibody studies were positive, but assays for voltage-gated calcium channel antibodies were negative. Low-amplitude baseline compound muscle action potentials combined with large incremental responses immediately after exercise were consistent with a presynaptic disorder. Thymic pathology in 1 patient was characteristic of autoimmune MG showing lymphoid follicular hyperplasia. No underlying malignancy was found in either patient. CONCLUSIONS: Patients with MG may rarely have presynaptic electrophysiologic abnormalities. This may occur even in the absence of the typical clinical and serologic features of the Lambert-Eaton syndrome. It is possible that there is another antibody present that is modulating presynaptic acetylcholine release.

Diagnosis and management of critical illness polyneuropathy and critical illness myopathy.

Newly acquired neuromuscular weakness commonly develops in the setting of critical illness. This weakness delays recovery and often causes prolonged ventilator dependence. An axonal sensory-motor polyneuropathy, critical illness polyneuropathy (CIP), is seen in up to a third of critically ill patients with the systemic inflammatory response syndrome (usually due to sepsis). As frequently, or more so, an acute myopathy, critical illness myopathy (CIM), develops in a similar setting, often in association with the use of corticosteroids and/or nondepolarizing neuromuscular-blocking agents. This paper reviews the clinical features, diagnostic approach, and treatment of CIP and CIM. There are no specific pharmacologic treatments for CIP or CIM, but recognizing the presence of one of these disorders often improves management. Prevention of CIP and CIM is feasible in part by avoiding risk factors and by aggressive medical management of critically ill patients. Intensive insulin therapy in intensive care unit patients appears to reduce the likelihood of developing CIP and/or CIM. Future treatments of sepsis may further reduce the incidence of these neuromuscular consequences of critical illness.

Value of repeated measures of nerve conduction and quantitative sensory testing in a diabetic neuropathy trial.

Conduct of a large, multicenter trial of the aldose reductase inhibitor zenarestat provided data on the reproducibility of multiple electrophysiologic (nerve conduction studies, NCS) and quantitative sensory (QST) tests. Baseline and 12-month electrophysiologic data from approximately 1100 patients at multiple centers were available for analysis. Intersite variability contributed minimally to overall test variance. All NCS tests were highly reproducible. Cool thermal and vibration QST thresholds, as measured by CASE IV instrumentation, were also highly reproducible. Intersubject variance accounted for the majority of variance for all parameters measured. Repeating NCS and QST measures decreased sample sizes needed to show statistical significance. Consideration of these observations, particularly with regard to QST, should aid in the design of future clinical trials investigating neuropathy.

Critical illness myopathy and polyneuropathy.

Neuromuscular weakness commonly develops in the setting of critical illness. This weakness delays recovery and often causes prolonged ventilator dependence. An axonal sensory-motor polyneuropathy, critical illness polyneuropathy (CIP), is seen in up to one third of critically ill patients with the systemic inflammatory response syndrome (usually due to sepsis). An acute myopathy, critical illness myopathy (CIM), frequently develops in a similar setting, often in association with the use of corticosteroids and/or nondepolarizing neuromuscular blocking agents. These patients are often difficult to evaluate due to the limitations imposed by the critical care setting and may be further complicated by the presence of both CIP and CIM in varying degrees. This paper reviews the clinical and electrophysiologic features of these disorders, as well as the putative pathophysiology. In the case of CIM, an animal model has provided evidence that weakness in this disorder is caused by muscle membrane inexcitability due to altered membrane sodium currents and loss of myosin thick filaments.

Involvement of skeletal muscle in dialysis-associated systemic fibrosis (nephrogenic fibrosing dermopathy).

Nephrogenic fibrosing dermopathy (NFD), a newly recognized scleroderma-like disease, was originally described as a purely cutaneous disorder. More widespread involvement, including fibrosis of pulmonary and cardiac tissues, has been documented only recently, and it has been suggested that a more appropriate designation is dialysis-associated systemic fibrosis. We report five cases of this novel disorder, spanning a spectrum of primarily skin to primarily muscle involvement. Clinical, radiological, electrophysiological, and pathological studies revealed moderate to severe fibrosis of striated muscles. All patients had end-stage renal failure on chronic dialysis, subacute to chronic hardening of the skin and muscles, restriction of limb movements with joint contractures, but normal to only mildly weak muscle strength. Limitation of movements was caused predominantly by skin tightness and induration, and by joint contractures rather than muscle weakness. Computerized tomography showed fibrosis of the fascia and muscles in the most severely affected patients, and electromyography showed mild to severe myopathic changes. Histopathology of affected muscles revealed a spectrum of mild to severe fibrosis, degenerating fibers, and chronic inflammatory cells. These results further support the contention that NFD is not a purely cutaneous disease, but is part of a larger systemic fibrotic process that may involve muscles.