Refractory generalized myasthenia gravis with myasthenic incomplete ophthalmoplegia successfully treated with eculizumab.

Purpose: This is a case of myasthenic incomplete ophthalmoplegia mimicking a partial cranial nerve 3 palsy both subjectively and objectively improving after treatment with eculizumab. Observations: We chronicle a case of severe generalized myasthenia gravis including myasthenia masquerading as a partial cranial nerve 3 palsy, refractory to pyridostigmine, mycophenolate, prednisone, intravenous immunoglobulin and plasma exchange but responsive to eculizumab. Conclusions and importance: This case demonstrates ocular and generalized myasthenia gravis refractory to several other therapies but amenable to eculizumab infusions, suggesting this medication may be of significant value in these difficult cases, and should be further explored for refractory ocular myasthenia gravis.

Costs and Utilization of New-to-Market Neurologic Medications.

BACKGROUND AND OBJECTIVES: The objective of this study was to compare the utilization and costs (total and out-of-pocket) of new-to-market neurologic medications with existing guideline-supported neurologic medications over time. METHODS: We used a healthcare pharmaceutical claims database (from 2001 to 2019) to identify patients with both a diagnosis of 1 of 11 separate neurologic conditions and either a new-to-market medication or an existing guideline-supported medication for that condition. Neurologic conditions included orthostatic hypotension, spinal muscular atrophy, Duchenne disease, Parkinson disease, multiple sclerosis, amyotrophic lateral sclerosis, myasthenia gravis, Huntington disease, tardive dyskinesia, transthyretin amyloidosis, and migraine. New-to-market medications were defined as all neurologic medications approved by the US Food and Drug Administration (FDA) between 2014 and 2018. In each year, we determined the median out-of-pocket and standardized total costs for a 30-day supply of each medication. We also measured the proportion of patients receiving new-to-market medications compared with all medications specific for the relevant condition. RESULTS: We found that the utilization of most new-to-market medications was small (<20% in all but 1 condition), compared with existing, guideline-supported medications. The out-of-pocket and standardized total costs were substantially larger for new-to-market medications. The median (25th percentile, 75th percentile) out-of-pocket costs for a 30-day supply in 2019 were largest for edaravone ($712.8 [$59.8-$802.0]) and eculizumab ($91.1 [$3.0-$3,216.4]). For new-to-market medications, the distribution of out-of-pocket costs was highly variable and the trends over time were unpredictable compared with existing guideline-supported medications. DISCUSSION: Despite the increasing number of FDA-approved neurologic medications, utilization of newly approved medications in the privately insured population remains small. Given the high costs and similar efficacy for most of the new medications, limited utilization may be appropriate. However, for new medications with greater efficacy, future studies are needed to determine whether high costs are a barrier to utilization.

Diagnostic characteristics of nerve conduction study parameters for vasculitic neuropathy.

INTRODUCTION/AIMS: In vasculitic neuropathy (VN), a 50% side-to-side difference in the amplitude of compound muscle action potentials and sensory nerve action potentials is considered meaningful, but unequivocal evidence is lacking. The aim of this study is to characterize electrodiagnostic features that best distinguish VN from other axonal polyneuropathies. METHODS: We conducted a case-control study between January 2000 and April 2021. We reviewed the records of patients with VN who had bilateral nerve conduction studies (NCS) and evaluated different electrodiagnostic models to help distinguish VN from non-inflammatory axonal polyneuropathies. RESULTS: We identified 82 cases, and 174 controls with non-inflammatory axonal neuropathies. The amplitude percent difference Z-score model showed the best discriminatory capability between cases and controls (area under the curve [AUC] 0.87; 95% confidence interval [CI] 0.82, 0.93), and the number of nerves tested did not significantly influence the model. Individually, the ulnar motor nerve (AUC 0.86; 95% CI 0.77, 0.94) and median motor nerve (AUC 0.85; 95% CI 0.77, 0.94) showed the best discriminatory capability. A 50% amplitude difference between at least two bilateral nerves, either in the upper (AUC 0.85; 95% CI 0.77, 0.93) or lower (AUC 0.79; 95% CI 0.71, 0.87) extremity showed good discriminatory threshold for detecting VN. DISCUSSION: The best electrodiagnostic criteria for VN utilizes z-scores of percent differences in nerve amplitudes, but this approach may be difficult to implement at the bedside. Alternately, a 50% amplitude difference in at least two nerves is a reasonable approximation.

Comparison of the United Kingdom and United States approaches to approval of new neuromuscular therapies.

Many novel therapies are now available for rare neuromuscular conditions that were previously untreatable. Hereditary transthyretin amyloidosis and spinal muscular atrophy are two examples of diseases with new medications that have transformed our field. The United States and the United Kingdom have taken disparate approaches to the approval and coverage of medications, despite both providing incentives to develop therapies targeting rare diseases. The US requires less evidence for approval when compared with medications for common diseases and does not have a mechanism to ensure or even encourage cost-effectiveness. The Institute of Clinical and Economic Review provides in-depth cost-effectiveness analyses in the US, but does not have the authority to negotiate drug costs. In contrast, the UK has maintained a similar scientific threshold for approval of all therapies, while requiring negotiation with National Institute for Health and Care Excellence to ensure that medications are cost-effective for rare diseases. These differences have led to approval of medications for rare diseases in the US that have less evidence than required for common diseases. Importantly, these medications have not been approved in the UK. Even when medications meet traditional scientific thresholds, they uniformly arrive with high list prices in the US, whereas they are available at cost-effective prices in the UK. The main downsides to the UK approach are that cost-effective medications are often available months later than in the US, and some medications remain unavailable.

Patients who meet electrodiagnostic criteria for CIDP rarely present with a sensory predominant DSP phenotype.

INTRODUCTION: It is unknown how often patients with electrodiagnostic evidence of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), a potentially treatable condition, present with a distal symmetric polyneuropathy (DSP) phenotype. METHODS: We reviewed the records of patients who presented to our electrodiagnostic laboratory between January 1, 2011, to December 31, 2019, and fulfilled electrodiagnostic criteria for CIDP to identify those who presented with a sensory predominant DSP phenotype. RESULTS: One hundred sixty-two patients had a chronic acquired demyelinating neuropathy, of whom 138 met criteria for typical or atypical CIDP. Nine of these patients presented with a sensory predominant DSP phenotype, among whom six were eventually diagnosed with distal acquired demyelinating symmetric (DADS) neuropathy; one with Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes (POEMS) syndrome; and two with idiopathic DSP. The prevalence of acquired chronic demyelinating neuropathies among all patients presenting with a DSP phenotype was estimated to be 0.34%. DISCUSSION: Patients who meet electrodiagnostic criteria for CIDP rarely present with a sensory predominant DSP phenotype, and electrodiagnostic testing rarely identifies treatable demyelinating neuropathies in patients who present with a DSP phenotype.

Diabetic neuropathy in children and youth: New and emerging risk factors.

Pediatric neuropathy attributed to metabolic dysfunction is a well-known complication in children and youth with type 1 diabetes. Moreover, the rise of obesity and in particular of type 2 diabetes may cause an uptick in pediatric neuropathy incidence. However, despite the anticipated increase in neuropathy incidence, pathogenic insights and strategies to prevent or manage neuropathy in the setting of diabetes and obesity in children and youth remain unknown. Data from adult studies and available youth cohort studies are providing an initial understanding of potential diagnostic, management, and preventative measures in early life. This review discusses the current state of knowledge emanating from these efforts, with particular emphasis on the prevalence, clinical presentation, diagnostic approaches and considerations, and risk factors of neuropathy in type 1 and type 2 diabetes in children and youth. Also highlighted are current management strategies and recommendations for neuropathy in children and youth with diabetes. This knowledge, along with continued and sustained emphasis on identifying and eliminating modifiable risk factors, completing randomized controlled trials to assess effectiveness of strategies like weight loss and exercise, and enhancing awareness to support early detection and prevention, are pertinent to addressing the rising incidence of neuropathy associated with diabetes and obesity in children and youth.

Diabetic neuropathy: what does the future hold?

Frustratingly, disease-modifying treatments for diabetic neuropathy remain elusive. Glycaemic control has a robust effect on preventing neuropathy in individuals with type 1 but not in those with type 2 diabetes, which constitute the vast majority of patients. Encouragingly, recent evidence points to new metabolic risk factors and mechanisms, and thus also at novel disease-modifying strategies, which are desperately needed. Obesity has emerged as the second most important metabolic risk factor for neuropathy (diabetes being the first) from consensus findings of seven observational studies in populations across the world. Moreover, dyslipidaemia and altered sphingolipid metabolism are emergent novel mechanisms of nerve injury that may lead to new targeted therapies. Clinical history and examination remain critical components of an accurate diagnosis of neuropathy. However, skin biopsies and corneal confocal microscopy are promising newer tests that have been used as outcome measures in research studies but have not yet demonstrated clear clinical utility. Given the emergence of obesity as a neuropathy risk factor, exercise and weight loss are potential interventions to treat and/or prevent neuropathy, although evidence supporting exercise currently outweighs data supporting weight loss. Furthermore, a consensus has emerged advocating tricyclic antidepressants, serotonin-noradrenaline (norepinephrine) reuptake inhibitors and gabapentinoids for treating neuropathic pain. Out-of-pocket costs should be considered when prescribing these medications since their efficacy and tolerability are similar. Finally, the downsides of opioid treatment for chronic, non-cancer pain are becoming increasingly evident. Despite these data, current clinical practice frequently initiates and continues opioid prescriptions for patients with neuropathic pain before prescribing guideline-recommended treatments.

A Self-Study Curriculum in Electromyography and Nerve Conduction Studies for Residents and Fellows.

INTRODUCTION: To our knowledge, there are no freely available curricula for a focused resident or fellow rotation in electromyography and nerve conduction studies that address the Accreditation Council for Graduate Medical Education (ACGME) milestones for neurology, physical medicine and rehabilitation, clinical neurophysiology, or neuromuscular medicine. Thus, we created this curriculum to help trainees develop a basic understanding of clinical electrodiagnostic studies. The program objectives map to many of the relevant ACGME milestones, primarily those pertaining to medical knowledge, patient care, and practice-based learning and improvement. METHODS: The curricular materials include an interactive, hyperlink-driven slide show with 19 educational modules, subdivided further into basic and advanced topics. We also created a 50-question multiple-choice test, paired each question with key concepts, and provided instructions on using the test results to develop a trainee-specific learning plan. RESULTS: Residents and fellows have been using this curriculum at the University of Michigan since 2007. The mean and median scores of 80 trainees who took the 50-item test between 2007 and 2016 were 80% and 82%, respectively, with a standard deviation of 10%. In annual surveys of neurology residents, this electromyography rotation has consistently had the highest mean approval rating of all clinical rotations in the training program. DISCUSSION: This curriculum is a complete, self-contained learning resource that may be used alone or to supplement a supervised apprenticeship for trainees who want to learn to perform electrodiagnostic studies independently. The content ensures that trainees demonstrate mastery of many of the ACGME milestones for their field.

Nerve conduction studies are safe in patients with central venous catheters.

INTRODUCTION: It is unknown if central venous catheters bypass the skin's electrical resistance and engender a risk of nerve conduction study-induced cardiac arrhythmia. The objective of this study is to determine if nerve conduction studies affect cardiac conduction and rhythm in patients with central venous catheters. METHODS: Under continuous 12-lead electrocardiogram monitoring, subjects with and without central venous catheters underwent a series of upper extremity nerve conduction studies. A cardiologist reviewed the electrocardiogram tracings for evidence of cardiac conduction abnormality or arrhythmia. RESULTS: Ten control subjects and 10 subjects with central venous catheters underwent the nerve conduction study protocol. No malignant arrhythmias or conduction abnormalities were noted in either group. CONCLUSIONS: Nerve conduction studies of the upper extremities, including both proximal stimulation and repetitive stimulation, do not appear to confer increased risk of cardiac conduction abnormality in those patients with central venous catheters who are not critically ill or have a prior history of arrhythmia. Muscle Nerve 56: 321-323, 2017.

Value of thyroid and rheumatologic studies in the evaluation of peripheral neuropathy.

Peripheral neuropathy is a common disorder, often prompting an extensive initial laboratory evaluation. The initial evaluation is particularly challenging to primary care physicians and neurologists because of the broad differential diagnosis. Although screening thyroid and rheumatologic tests are frequently ordered, the diagnostic yield of these tests is unclear. Data from our institution were collected on patient demographics, clinical characteristics including warning signs suggestive of a diagnosis other than distal symmetric polyneuropathy, history of thyroid or rheumatologic disease, and laboratory tests ordered. Thyroid and rheumatologic screening tests are commonly ordered in the evaluation of peripheral neuropathy. Our findings suggest a low aggregate value of these tests based on low yield and infrequent changes in the suspected etiology or management of these patients.

Polyneuropathy associated with the diffuse infiltrative lymphocytosis syndrome.

Diffuse infiltrative lymphocytosis syndrome (DILS) arises in HIV-positive patients secondary to infiltration of lymphocytes into the peripheral tissues and produces the disease's characteristic symptoms-parotid gland enlargement and a sicca syndrome. Many patients, however, first seek medical attention for treatment of the extraglandular manifestations of DILS, most commonly interstitial pneumonitis. In this case report, we describe an atypical presentation of DILS characterized by polyradiculoneuropathy in the absence of parotid gland enlargement or interstitial pneumonitis. Minor salivary gland biopsy of the patient's lip confirmed a chronic inflammatory state with lymphoid aggregates within the minor salivary glands. He was started on prednisone with immediate improvement in his symptoms. This report illustrates for clinicians the diverse extraglandular manifestations of DILS and underscores the importance of considering it in the differential diagnosis of HIV-positive patients with a preserved CD4 count who present with peripheral neuropathy.

Adult-to-adult living donor liver transplantation.

The present review outlines the principles of living donor liver transplantation, donor workup, procedure and outcomes. Living donation offers a solution to the growing gap between the need for liver transplants and the limited availability of deceased donor organs. With a multidisciplinary team focused on donor safety and experienced surgeons capable of performing complex resection/reconstruction procedures, donor morbidity is low and recipient outcomes are comparable with results of deceased donor transplantation.

RhoC-GTPase is a novel tissue biomarker associated with biologically aggressive carcinomas of the breast.

BACKGROUND: There is a need for reliable predictors of breast cancer aggressiveness that will further refine the staging classification and help guide the implementation of novel therapies. We have identified RhoC as being nearly always overexpressed in the most aggressive form of breast cancer, inflammatory breast cancer (IBC); in subsequent work we identified RhoC to be a promising marker of aggressive behavior in breast cancers less than 1 cm in diameter. We hypothesized that RhoC expression would identify aggressive, non-IBC tumors breast cancer patients at any stage with worse outcomes defined as recurrence and/or metastasis. METHODS: We constructed four high-density tissue microarrays (TMAs) using 801 tissue cores from 280 patients. These tissues represent a wide range of normal breast and breast disease, including intraductal hyperplasia, ductal carcinoma in situ (DCIS), invasive carcinomas, and distant metastases. The TMAs were immunostained using a polyclonal anti-RhoC antibody developed in our laboratory. Cytoplasmic RhoC expression was scored as negative, weak, moderate, or strong by a previously validated scoring schema. RESULTS: RhoC expression increases with breast cancer progression. All samples of normal breast epithelium had negative to weak staining, whereas staining intensity increased in hyperplasia, DCIS, invasive carcinoma, and metastases (Kruskal-Wallis p < 0.001). In patients with invasive carcinoma, high RhoC expression was associated with features of aggressive behavior including high histologic grade, positive lymph nodes, and negative hormonal receptor status. High RhoC expression was a predictor of overall survival in patients with breast cancer (log rank test, p = 0.002) and was associated with 100% increase in the risk of death as compared to patients with low RhoC expression. Importantly, high RhoC was an independent predictor of poor response to doxorubicin-based chemotherapy with a hazard ratio of 3.1 and a 95% CI of 1.2-7.7 (p = 0.02). CONCLUSION: RhoC expression increases with breast cancer progression and RhoC protein level in tumor tissue is strongly associated with biologically aggressive invasive carcinomas of the breast. RhoC expression, if validated, may identify patients who are less likely benefit from doxorubicin therapy and suggests RhoC overexpression as a new target for intervention.

WISP3 and RhoC guanosine triphosphatase cooperate in the development of inflammatory breast cancer.

BACKGROUND: Inflammatory breast cancer (IBC) is the most lethal form of locally advanced breast cancer. We found concordant and consistent alterations of two genes in 90% of IBC tumors when compared to stage matched, non-IBC tumors: overexpression of RhoC GTPase and loss of WISP3. Further work revealed that RhoC is a transforming oncogene for HME cells. Despite the aggressiveness of the RhoC-driven phenotype, it does not quantitatively reach that of the true IBC tumors. We have demonstrated that WISP3 has tumor growth and angiogenesis inhibitory functions in IBC. We hypothesized that RhoC and WISP3 cooperate in the development of IBC. METHODS: Using an antisense approach, we blocked WISP3 expression in HME cells (HME/AS WISP3). Cellular proliferation and anchorage independent growth were determined using the MTT assay and the anchorage independent growth in soft agar assay. VEGF was measured in the conditioned media of the HME/ AS WISP3 by ELISA. RESULTS: Antisense inhibition of WISP3 expression in HME cells increased the levels of RhoC mRNA and increased cellular proliferation, anchorage independent growth and secretion of VEGF in these cells. Conversely, restoration of WISP3 expression in the highly malignant IBC cell line SUM149 was able to decrease the expression of RhoC protein. CONCLUSION: WISP3 modulates RhoC expression in HME cells and in the IBC cell line SUM149, and provide further evidence in support that these two genes act in concert to give rise to the highly aggressive IBC phenotype. We propose a model of this interaction as a starting point for further investigations.