AMPK governs lineage specification through Tfeb-dependent regulation of lysosomes.

Faithful execution of developmental programs relies on the acquisition of unique cell identities from pluripotent progenitors, a process governed by combinatorial inputs from numerous signaling cascades that ultimately dictate lineage-specific transcriptional outputs. Despite growing evidence that metabolism is integrated with many molecular networks, how pathways that control energy homeostasis may affect cell fate decisions is largely unknown. Here, we show that AMP-activated protein kinase (AMPK), a central metabolic regulator, plays critical roles in lineage specification. Although AMPK-deficient embryonic stem cells (ESCs) were normal in the pluripotent state, these cells displayed profound defects upon differentiation, failing to generate chimeric embryos and preferentially adopting an ectodermal fate at the expense of the endoderm during embryoid body (EB) formation. AMPK(-/-) EBs exhibited reduced levels of Tfeb, a master transcriptional regulator of lysosomes, leading to diminished endolysosomal function. Remarkably, genetic loss of Tfeb also yielded endodermal defects, while AMPK-null ESCs overexpressing this transcription factor normalized their differential potential, revealing an intimate connection between Tfeb/lysosomes and germ layer specification. The compromised endolysosomal system resulting from AMPK or Tfeb inactivation blunted Wnt signaling, while up-regulating this pathway restored expression of endodermal markers. Collectively, these results uncover the AMPK pathway as a novel regulator of cell fate determination during differentiation.

Episodic and Chronic Migraine in Primary Care.

OBJECTIVE: To inform migraine care model development by assessing differences between patients with chronic migraine (CM) and episodic migraine (EM) in the current state of treatment, disability, patient satisfaction, and quality improvement opportunities. BACKGROUND: Efficient and focused use of scarce resources will be needed to address challenges within large populations of migraine patients. METHODS: We deployed a cross-sectional survey study of randomly selected migraine patients within a community primary care practice. RESULTS: There were 516 survey respondents (516/1804 [30%] response rate). CM patients were more likely than EM patients to report care from a neurologist (76/110 [69%] vs 229/406 [56%]; P = .0026), and higher disability according to the Migraine Disability Assessment and Headache Impact Test - 6 questionnaires (P < .0001). CM patients were less likely than EM patients to report overall satisfaction with care (16/110 [38%] vs 156/406 [66%], P = .0002), satisfaction with access to care (17/110 [33%] vs 176/406 [68%], P < .0001), and advice they needed (16/110 [31%] vs 160/406 [62%], P < .0001). Most patients with migraine had been offered triptan medications 377/516 (78%). Overall, 156/516 (31%) of individuals were currently taking any medication for migraine prevention, and 208/516 (40%) including botulinum toxin injections. CM patients were more likely to be taking preventive medication (39/110 [36%] vs 117/406 [29%], P = .0191) and report familiarity with the diagnosis of medication-overuse headache than patients with EM (80/110 [81%] vs 256/406 [69%], P = .0178). CONCLUSIONS: We observed differences between patients with chronic and EM and expected care delivery improvement opportunities for migraine patients in primary care. CM patients report higher levels of disability and less satisfaction with access to perceived needed medical advice and care. These findings support the need to further develop and study novel care models to efficiently and effectively deliver high-quality care and expertise in limited supply to a diverse migraine population.

Neuroimaging utilization and findings in headache outpatients: Significance of red and yellow flags.

Background Neuroimaging for headache commonly exceeds published guideline recommendations and may be overutilized. Methods We conducted a retrospective cross-sectional study of all outpatient community patients at Mayo Clinic Rochester who underwent a neuroimaging study for a headache indication in 2015. We assessed the neuroimaging utilization pattern, clinical application of red flags, and concordance with neuroimaging guidelines. Results We identified 190 outpatients who underwent 304 neuroimaging studies for headache. The median age was 46.5 years (range 18-91 years), 65% were female, and most reported no prior history of headache (n = 97, 51%). A minority of patients had prior brain imaging studies (n = 44, 23%) and neurological consultations for headache (n = 29, 15%). Few studies were ordered after consultation with a neurologist (n = 14, 7%). Seventy-seven percent of patients were documented to have a "red flag" justifying the imaging study. Abnormal neuroimaging findings were found in 3.1% of patients with warning flags (5/161); carotid dissection (n = 3) and reversible cerebral vasoconstrictive syndrome (n = 2). An estimated 35% of patients were imaged against guidelines. Conclusions The prevalence of serious causes of headache in a community practice was low despite the presence of a documented red flag symptom. Inadequate understanding or application of red flags may be contributing to recommendations to image patients against current guidelines. Interventions to reduce unnecessary neuroimaging of patients with headache need to be designed and implemented.

Impact of Multiple Chronic Conditions in Patients Hospitalized with Stroke and Transient Ischemic Attack.

BACKGROUND: The prevalence and clinical impact of chronic conditions (CCs) have increasingly been recognized as an important public health concern. We evaluated the prevalence of coexisting CCs and their association with 30-day mortality and readmission in hospitalized patients with stroke and transient ischemic attack (TIA). METHODS: In a retrospective study of patients aged ≥18 years hospitalized for first-ever stroke and TIA, we assessed the prevalence of coexisting CCs and their predictive value for subsequent 30-day mortality and readmission. RESULTS: Study cohort comprised 6771 patients, hospitalized for stroke (n = 4068) and TIA (n = 2703), 51.4% men, with mean age of 68.2 years (standard deviation: ±15.6), mean number of CCs of 2.9 (±1.7), 30-day mortality rate of 8.6% (entire cohort), and 30-day readmission rate of 9.7% (in 2498 patients limited to Olmsted and surrounding counties). In multivariable models, significant predictors of (1) 30-day mortality were coexisting heart failure (HF) (odds ratio [OR]: 1.45, 95% confidence interval [CI]: 1.09-1.92), cardiac arrhythmia (OR: 1.74, 95% CI: 1.40-2.17), coronary artery disease (CAD) (OR: 1.64, 95% CI: 1.29-2.08), cancer (OR: 1.67, 95% CI: 1.31-2.14), and diabetes (HR: 1.28, 95% CI: 1.01-1.62); and (2) 30-day readmission (n = 2498) were CAD (OR: 1.50, 95% CI: 1.09-2.07), cancer (OR: 1.46, 95% CI: 1.01-2.10), and arthritis (OR: 1.62, 95% CI: 1.09-2.40). CONCLUSIONS: In patients hospitalized with stroke and TIA, CCs are highly prevalent and influence 30-day mortality and readmission. Optimal therapeutic and lifestyle interventions for CAD, HF, cardiac arrhythmia, cancer, diabetes, and arthritis may improve early clinical outcome.

A spatially and temporally restricted mouse model of soft tissue sarcoma.

Soft tissue sarcomas are mesenchymal tumors that are fatal in approximately one-third of patients. To explore mechanisms of sarcoma pathogenesis, we have generated a mouse model of soft tissue sarcoma. Intramuscular delivery of an adenovirus expressing Cre recombinase in mice with conditional mutations in Kras and Trp53 was sufficient to initiate high-grade sarcomas with myofibroblastic differentiation. Like human sarcomas, these tumors show a predilection for lung rather than lymph node metastasis. Using this model, we showed that a prototype handheld imaging device can identify residual tumor during intraoperative molecular imaging. Deletion of the Ink4a-Arf locus (Cdkn2a), but not Bak1 and Bax, could substitute for mutation of Trp53 in this model. Deletion of Bak1 and Bax, however, was able to substitute for mutation of Trp53 in the development of sinonasal adenocarcinoma. Therefore, the intrinsic pathway of apoptosis seems sufficient to mediate p53 tumor suppression in an epithelial cancer, but not in this model of soft tissue sarcoma.

Electronic Consultations in a Community Neurology Practice: A Retrospective Study Informing Best Practice.

Objective: To describe our practice of electronic consultations (e-consults) and assess safety and risk factors for subsequent face-to-face consultations. Patients and Methods: A retrospective cohort study of all e-consults completed in a community neurology practice between May 5, 2018, and June 31, 2019, was completed. Clinical and demographic variables were compared between the successful and unsuccessful (defined by presence of subsequent face-to-face consultation) cohorts. Hazard ratios (HR) were calculated using Cox regression model. Kaplan-Meier probability analysis (with 95% CIs) of subsequent face-to-face consultation was performed. Case examples highlighting potential harm were summarized. Results: In total, 302 e-consults were reviewed. The most frequent referrals were for headache (n=125, 41.4%), dysesthesia (n=40, 13.2%), and abnormal imaging finding (n=27, 8.9%). The most common e-consult questions were for treatment (57.6%) and diagnostic evaluation (48.0%) recommendations. Moreover, 24.8% (n=75) of e-consults were followed by face-to-face consultations, with primary risk factors including female sex (HR, 1.9), referral for headache (HR, 1.7), and final diagnosis of migraine (HR, 2.0) or long-term migraine (HR, 5.0). Potential harm related to delayed diagnosis/treatment was identified in 6 (2.0%) patients with migraine and 4 (1.3%) without migraine presenting to emergency department. Conclusion: Utilization of e-consults may safely improve access to neurologic expertise and prevent the need for some visits, which may have required a face-to-face visit. In patients with chronic migraine, e-consults should be considered short-term and followed by face-to-face consultation as soon as access allows. Neurologists performing e-consults should be able to triage patients to face-to-face consultation, particularly when diagnosis is uncertain or the neurologic examination may help guide appropriate testing.

Tissue-specific p19Arf regulation dictates the response to oncogenic K-ras.

The ability of oncogenes to engage tumor suppressor pathways represents a key regulatory mechanism that can limit the outgrowth of incipient tumor cells. For example, in a number of settings oncogenic Ras strongly activates the Ink4a/Arf locus, resulting in cell cycle arrest or senescence. The capacity of different cell types to execute tumor suppressor programs following expression of endogenous K-ras(G12D) in vivo has not been examined. Using compound mutant mice containing the Arf(GFP) reporter and the spontaneously activating K-ras(LA2) allele, we have uncovered dramatic tissue specificity of K-ras(G12D)-dependent p19(Arf) up-regulation. Lung tumors, which can arise in the presence of functional p19(Arf), rarely display p19(Arf) induction. In contrast, sarcomas always show robust activation, which correlates with genetic evidence, suggesting that loss of the p19(Arf)-p53 pathway is a requisite event for sarcomagenesis. Using constitutive and inducible RNAi systems in vivo, we highlight cell type-specific chromatin regulation of Ink4a/Arf as a critical determinant of cellular responses to oncogenic K-ras. Polycomb-group complexes repress the locus in lung tumors, whereas the SWI/SNF family member Snf5 acts as an important mediator of p19(Arf) induction in sarcomas. This variation in tumor suppressor induction might explain the inherent differences between tissues in their sensitivity to Ras-mediated transformation.

Posttraumatic Ruptured Axillary Mononeuropathy Without Shoulder Dislocation in an American Football Player: A Case Report and Review of the Literature.

ABSTRACT: A high school-aged right-handed adolescent boy presented with a 5-mo history of persistent proximal right arm weakness and numbness after an American football stinger injury without a documented history of a shoulder dislocation or humeral fracture. He developed diffuse deltoid muscle atrophy, persistent shoulder abduction weakness, and reduced pinprick sensation confined to the axillary distribution over 5 mos. Needle electromyography demonstrated dense fibrillation potentials and no voluntary activation in all three deltoid muscle heads, indicating a severe posttraumatic ruptured axillary mononeuropathy. The patient then underwent a complex three-cable sural nerve graft repair for attempted reinnervation of the axillary-innervated muscles. Isolated axillary nerve injuries are usually associated with anterior shoulder dislocations; however, a severe isolated persistent axillary mononeuropathy from a ruptured axillary nerve may occur in trauma patients without a clear history of shoulder dislocation. These patients may present with only mild persistent weakness of shoulder abduction. Electrodiagnostic testing to fully assess axillary nerve function should still be considered to identify patients with high-grade nerve injuries that may benefit from sural nerve grafting. The rapid recovery of our patient's initial symptoms with persistent severe axillary injury suggests a unique vulnerability of the nerve due to the neuroanatomy and possibly other factors.

Migraine Patient Care Model Preferences in a Community Practice.

Background and Objectives: Developing high-value care models with limited resources for large populations of individuals with migraine requires advanced understanding of patient preferences for care delivery methods. In this study, we aimed to inform the development of migraine care models by assessing patient preferences for types of care delivery and determining differences based on migraine frequency and disability. Methods: We analyzed unpublished data from a cross-sectional survey of 516 randomly selected individuals with migraine within a community practice associated with Mayo Clinic, Rochester, MN. Results: Individuals with chronic migraine, compared with those with episodic migraine, were more likely to prefer a visit with a neurologist (p = 0.0005), synchronous telephone conference with primary care provider (PCP) and neurologist (p = 0.0102), and a written migraine action plan in the medical record (p = 0.0343). Compared with those with mild/no disability, individuals with moderate-to-severe disability were more likely to prefer a visit with a neurologist (p < 0.0001), synchronous video or telephone conference with PCP and neurologist (p < 0.0001), PCP communication with neurologist (p = 0.0099), electronic message to primary care team with access to neurologist (p = 0.0216), and written action plan in the medical record (p = 0.0011). Collectively, individuals most preferred telephone follow-up and least preferred communications with a nurse or pharmacist or generalized education (all p < 0.001). Discussion: We observed differences in migraine care delivery preferences between migraine frequency and level of migraine disability. Observations support development of care pathways that include a written migraine action plan, primary care-neurology collaboration including nontraditional interactions, and prioritization of traditional neurology consultation for the most disabled patients.

Feasibility and Usability of a Mobile App-Based Interactive Care Plan for Migraine in a Community Neurology Practice: Development and Pilot Implementation Study.

BACKGROUND: Migraine is a common and major cause of disability, poor quality of life, and high health care use. Access to evidence-based migraine care is limited and projected to worsen. Novel mobile health app-based tools may effectively deliver migraine patient education to support self-management, facilitate remote monitoring and treatment, and improve access to care. The risk that such an intervention may increase the care team workload is a potential implementation barrier. OBJECTIVE: This study aims to describe a novel electronic health record-integrated mobile app-based Migraine Interactive Care Plan (MICP) and evaluate its feasibility, usability, and impact on care teams in a community neurology practice. METHODS: Consecutive enrollees between September 1, 2020, and February 16, 2022, were assessed in a single-arm observational study of usability, defined by 74.3% (127/171) completing ≥1 assigned task. Task response rates, rate and type of care team escalations, and patient-reported outcomes were summarized. Patients were prospectively recruited and randomly assigned to routine care with or without the MICP from September 1, 2020, to September 1, 2021. Feasibility was defined by equal to or fewer downstream face-to-face visits, telephone contacts, and electronic messages in the MICP cohort. The Wilcoxon rank-sum test was used to compare continuous variables, and the chi-square test was used for categorical variables for those with at least 3 months of follow-up. RESULTS: A total of 171 patients were enrolled, and of these, 127 (74.3%) patients completed ≥1 MICP-assigned task. Mean escalations per patient per month was 0.9 (SD 0.37; range 0-1.7). Patient-confirmed understanding of the educational materials ranged from 26.6% (45/169) to 56.2% (95/169). Initial mean headache days per week was 4.54 (SD 2.06) days and declined to 2.86 (SD 1.87) days at week 26. The percentage of patients reporting favorable satisfaction increased from a baseline of 35% (20/57) to 83% (15/18; response rate of 42/136, 30.9% to 28/68, 41%) over the first 6 months. A total of 121 patients with MICP were compared with 62 patients in the control group. No differences were observed in the rate of telephone contacts or electronic messages. Fewer face-to-face visits were observed in the MICP cohort (13/121, 10.7%) compared with controls (26/62, 42%; P<.001). CONCLUSIONS: We describe the successful implementation of an electronic health record-integrated mobile app-based care plan for migraine in a community neurology practice. We observed fewer downstream face-to-face visits without increasing telephone calls, medication refills, or electronic messages. Our findings suggest that the MICP has the potential to improve patient access without increasing care team workload and the need for patient input from diverse populations to improve and sustain patient engagement. Additional studies are needed to assess its impact in primary care.

Human Induced Pluripotent Stem Cell Encapsulation Geometry Impacts Three-Dimensional Developing Human Engineered Cardiac Tissue Functionality.

Cardiac tissue engineering has been working to alleviate the immense burden of cardiovascular disease for several decades. To improve cardiac tissue homogeneity and cardiomyocyte (CM) maturation, in this study, we investigated altering initial encapsulation geometry in a three-dimensional (3D) direct cardiac differentiation platform. Traditional engineered cardiac tissue production utilizes predifferentiated CMs to produce 3D cardiac tissue and often involves various cell selection and exogenous stimulation methods to promote CM maturation. Starting tissue formation directly with human induced pluripotent stem cells (hiPSCs), rather than predifferentiated CMs, simplifies the engineered cardiac tissue formation process, making it more applicable for widespread implementation and scale-up. In this study, hiPSCs were encapsulated in poly (ethylene glycol)-fibrinogen in three tissue geometries (disc-shaped microislands, squares, and rectangles) and subjected to established cardiac differentiation protocols. Resulting 3D engineered cardiac tissues (3D-ECTs) from each geometry displayed similar CM populations (∼65%) and gene expression over time. Notably, rectangular tissues displayed less tissue heterogeneity and suggested more advanced features of maturing CMs, including myofibrillar alignment and Z-line formation. In addition, rectangular tissue showed significantly higher anisotropic contractile properties compared to square and microisland tissues (MI 0.28 ± 0.03, SQ 0.35 ± 0.05, RT 0.79 ± 0.04). This study demonstrates a straightforward method for simplifying and improving 3D-ECT production without the use of exogenous mechanical or electrical pacing and has the potential to be utilized in bioprinting and drug testing applications. Impact statement Current methods for improving cardiac maturation postdifferentiation remain tedious and complex. In this study, we examined the impact of initial encapsulation geometry on improvement of three-dimensional engineered cardiac tissue (3D-ECT) production and postdifferentiation maturation for three tissue geometries, including disc-shaped microislands, squares, and rectangles. Notably, rectangular 3D-ECTs displayed less tissue heterogeneity and more advanced features of maturing cardiomyocytes, including myofibrillar alignment, Z-line formation, and anisotropic contractile properties, compared to microisland and square tissues. This study demonstrates an initial human induced pluripotent stem cell-encapsulated rectangular tissue geometry can improve cardiac maturation, rather than implementing cell selection or tedious postdifferentiation manipulation, including exogenous mechanical and/or electrical pacing.

Perivenous demyelination: association with clinically defined acute disseminated encephalomyelitis and comparison with pathologically confirmed multiple sclerosis.

Distinction between acute disseminated encephalomyelitis and acute multiple sclerosis is often clinically difficult. Perivenous demyelination is the pathological hallmark of acute disseminated encephalomyelitis, whereas confluent demyelination is the hallmark of acute multiple sclerosis. We investigated whether perivenous demyelination versus confluent demyelination distinguishes acute disseminated encephalomyelitis from multiple sclerosis. Patients with perivenous demyelination (n = 13; median age 43 years, range 5-67) on brain biopsy and/or autopsy, ascertained retrospectively, were compared with a cohort with confluent demyelination only (n = 91; 84% multiple sclerosis, 16% isolated syndrome at follow-up; median age 39 years, range 10-69). Clinical presentation, course and the International Paediatric Multiple Sclerosis Study Group clinical criteria for acute disseminated encephalomyelitis were assessed in both cohorts. Among the perivenous demyelination cohort, 10 patients had only perivenous demyelination and three also had confluent demyelination. All but one patient with perivenous demyelination only had a monophasic course, whereas two of three with both types had a relapsing course. The perivenous demyelination cohort was more likely than the confluent demyelination cohort to present with encephalopathy (P < 0.001), depressed level of consciousness (P < 0.001), headache (P < 0.001), meningismus (P = 0.04), cerebrospinal fluid pleocytosis (P = 0.04) or multifocal enhancing magnetic resonance imaging lesions (P < 0.001). A distinct pattern of cortical microglial activation and aggregation without associated cortical demyelination was found among six perivenous demyelination patients, all of whom had encephalopathy and four of whom had depressed level of consciousness. This pattern of cortical pathology was not observed in the confluent demyelination cohort, even in one patient with depressed level of consciousness. Clinical criteria were 80% sensitive and 91% specific for pathologically defined acute disseminated encephalomyelitis (perivenous demyelination), but misdiagnosed acute disseminated encephalomyelitis among 9% of patients with confluent demyelination and multiple sclerosis diagnosis at last follow-up. Perivenous demyelination is associated with meningoencephalopathic presentations and a monophasic course. Depressed level of consciousness is a more specific clinical criterion for pathologically confirmed acute disseminated encephalomyelitis than encephalopathy, which over-diagnosed acute disseminated encephalomyelitis among multiple sclerosis patients. A distinct pattern of cortical microglial activation without cortical demyelination may be the pathological correlate of depressed level of consciousness in acute disseminated encephalomyelitis. Although pathological evidence of perivenous demyelination may be superior to clinical criteria for diagnosing acute disseminated encephalomyelitis, the co-occurrence of perivenous and confluent demyelination in some individuals suggests pathogenic overlap between acute disseminated encephalomyelitis and multiple sclerosis and misclassification even with biopsy.

Zotatifin, an eIF4A-Selective Inhibitor, Blocks Tumor Growth in Receptor Tyrosine Kinase Driven Tumors.

Oncoprotein expression is controlled at the level of mRNA translation and is regulated by the eukaryotic translation initiation factor 4F (eIF4F) complex. eIF4A, a component of eIF4F, catalyzes the unwinding of secondary structure in the 5'-untranslated region (5'-UTR) of mRNA to facilitate ribosome scanning and translation initiation. Zotatifin (eFT226) is a selective eIF4A inhibitor that increases the affinity between eIF4A and specific polypurine sequence motifs and has been reported to inhibit translation of driver oncogenes in models of lymphoma. Here we report the identification of zotatifin binding motifs in the 5'-UTRs of HER2 and FGFR1/2 Receptor Tyrosine Kinases (RTKs). Dysregulation of HER2 or FGFR1/2 in human cancers leads to activation of the PI3K/AKT and RAS/ERK signaling pathways, thus enhancing eIF4A activity and promoting the translation of select oncogenes that are required for tumor cell growth and survival. In solid tumor models driven by alterations in HER2 or FGFR1/2, downregulation of oncoprotein expression by zotatifin induces sustained pathway-dependent anti-tumor activity resulting in potent inhibition of cell proliferation, induction of apoptosis, and significant in vivo tumor growth inhibition or regression. Sensitivity of RTK-driven tumor models to zotatifin correlated with high basal levels of mTOR activity and elevated translational capacity highlighting the unique circuitry generated by the RTK-driven signaling pathway. This dependency identifies the potential for rational combination strategies aimed at vertical inhibition of the PI3K/AKT/eIF4F pathway. Combination of zotatifin with PI3K or AKT inhibitors was beneficial across RTK-driven cancer models by blocking RTK-driven resistance mechanisms demonstrating the clinical potential of these combination strategies.

Targeting Oncogene mRNA Translation in B-Cell Malignancies with eFT226, a Potent and Selective Inhibitor of eIF4A.

The PI3K/AKT/mTOR pathway is often activated in lymphoma through alterations in PI3K, PTEN, and B-cell receptor signaling, leading to dysregulation of eIF4A (through its regulators, eIF4B, eIF4G, and PDCD4) and the eIF4F complex. Activation of eIF4F has a direct role in tumorigenesis due to increased synthesis of oncogenes that are dependent on enhanced eIF4A RNA helicase activity for translation. eFT226, which inhibits translation of specific mRNAs by promoting eIF4A1 binding to 5'-untranslated regions (UTR) containing polypurine and/or G-quadruplex recognition motifs, shows potent antiproliferative activity and significant in vivo efficacy against a panel of diffuse large B-cell lymphoma (DLBCL), and Burkitt lymphoma models with ≤1 mg/kg/week intravenous administration. Evaluation of predictive markers of sensitivity or resistance has shown that activation of eIF4A, mediated by mTOR signaling, correlated with eFT226 sensitivity in in vivo xenograft models. Mutation of PTEN is associated with reduced apoptosis in vitro and diminished efficacy in vivo in response to eFT226. In models evaluated with PTEN loss, AKT was stimulated without a corresponding increase in mTOR activation. AKT activation leads to the degradation of PDCD4, which can alter eIF4F complex formation. The association of eFT226 activity with PTEN/PI3K/mTOR pathway regulation of mRNA translation provides a means to identify patient subsets during clinical development.

Absent, unrecognized, and minimal myotonic discharges in myotonic dystrophy type 2.

The purpose of this study was to describe the frequency of absent, unrecognized, or minimal myotonic discharges (MDs) in myotonic dystrophy type 2 (DM2). We performed a retrospective review of needle electromyography (EMG) data prior to genetic diagnosis in 49 DM2 patients at the Mayo Clinic. MDs were not reported on first or repeat EMG studies (n = 8) and not found in archived recordings of 4 patients (8%); archived EMG recordings (n = 4) confirmed the absence of MDs (n = 2), including 1 patient with normal insertional activity in all muscles, and misinterpretation of MDs as slow fibrillation potentials (n = 1) and complex repetitive discharge (CRD) activity (n = 1). Eight (16%) patients had minimal classic MDs with diffusely increased insertional activity, including waning-only MDs in all patients in this group with archived EMG recordings (n = 5). Diffuse MDs were found in 33 (67%) patients. Absent or minimal MDs do not exclude DM2. Over-reliance on diffuse MDs in patients who present with myopathy may lead to delay in genetic diagnosis of DM2.

Sporadic late onset nemaline myopathy responsive to IVIg and immunotherapy.

Sporadic late onset nemaline myopathy (SLONM) is a progressive myopathy of indeterminate etiology and poor outcome. If associated with a monoclonal gammopathy, SLONM carries a more unfavorable prognosis. Immunotherapy was unsuccessful. We report two HIV-negative SLONM/monoclonal gammopathy patients who improved following intravenous immunoglobulin (IVIg) treatment alone or in combination with immunosuppressant agents. This favorable response to treatment suggests that a dysimmune mechanism is operative in some SLONM individuals. We suggest that IVIg deserves initial consideration for SLONM therapy.

Gadolinium enhancement of the lumbar roots in a case of ALS.

We present a single case of clinically definite amyotrophic lateral sclerosis (ALS) associated with modest gadolinium enhancement of the lumbar nerve roots without thickening or nodularity and with CSF protein elevation (80 mg/dl). These findings should not exclude a clinical diagnosis of ALS and suggest that the enhancement of nerve roots and protein elevation were related to rapid neuronal degeneration, not inflammation.

Factors Associated With Risk of Recurrent Transient Global Amnesia.

Importance: Transient global amnesia (TGA) is usually considered a benign event with a low recurrence rate. However, recurrence rates vary considerably among studies and there are no known risk factors for TGA. Objective: To examine risk factors for the recurrence of TGA. Design, Setting, and Participants: This retrospective cohort study involved medical record review of patients with isolated or recurrent TGA presenting to the Mayo Clinic in Rochester, Minnesota, between August 1, 1992, and February 28, 2018. A total of 1491 cases were reviewed and 1044 met diagnostic inclusion criteria for TGA, with the remainder excluded owing to indeterminate or alternate diagnoses or limited information available in the medical record. Exposures: Single vs recurrent episodes of TGA. Main Outcomes and Measures: Demographics, precipitating factors, migraine history, imaging and electrodiagnostic findings, and family history of TGA were collected. The main outcome measure was TGA recurrence. Results: Of 1044 included patients, 575 (55.1%) were male, and the mean (SD) age at inclusion was 75.0 (11.5) years. A total of 901 patients (86.3%) had a single episode of TGA and 143 (13.7%) had recurrent episodes of TGA. The 2 groups were similar in age at inclusion, sex, identifiable triggers, and duration of anterograde amnesia. The number of recurrences ranged from 1 to 9, with 137 individuals (95.8%) having 3 or fewer recurrences. The mean (SD) age at first episode of TGA was 65.2 (10.0) years for individuals with a single episode vs 58.8 (10.3) years for those with recurrent episodes (P < .001). There was a personal history of migraine in 180 individuals (20.0%) with a single episode of TGA and 52 individuals (36.4%) with recurrent episodes of TGA (P < .001), and a family history of migraine in 167 individuals (18.5%) with a single episode of TGA and 44 individuals (30.8%) with recurrent episodes of TGA (P = .001). There were no electroencephalographic findings associated with increased risk of TGA recurrence. Acute and subacute temporal lobe abnormalities on results of magnetic resonance imaging were seen rarely and did not require intervention. A family history of TGA was identified in 12 individuals (1.3%) with a single episode of TGA and 4 individuals (2.8%) with recurrent episodes of TGA. Conclusions and Relevance: This study suggests that, in this large cohort of patients with TGA, recurrent TGA was associated with earlier age at the time of first TGA episode and higher prevalence of both personal and family history of migraine compared with isolated cases. These results can be used to counsel patients about risks of recurrence and may have implications for the understanding of TGA pathophysiology.

Spontaneous Vertebral Arteriovenous Fistula Mimicking Brachial Radiculoplexopathy.

BACKGROUND: Vertebral arteriovenous fistulas (VAVFs) are uncommon high-flow communications between a vertebral artery and surrounding venous plexus that occur spontaneously or secondary to trauma. CASE DESCRIPTION: A woman aged 57 years presented with a multiday history of rapidly progressive numbness and weakness in the left C5-C6 dermomyotomes. Her physical examination findings and subsequent electrophysiological testing were suggestive of a brachial radiculoplexopathy. Noninvasive imaging demonstrated venous congestion with multilevel compromise of the left-sided cervical foramina, and subsequent vertebral angiography confirmed a VAVF, which was treated with trapping of the involved vertebral artery segment. Her numbness and weakness progressively improved with concurrent involution of the dilated veins. CONCLUSIONS: This is a rare case of VAVF manifesting as a brachial radiculoplexopathy. Although rare, VAVF may be considered as a potential cause in patients presenting with similar symptoms.