Low-grade B-cell lymphoma of the central nervous system with plasmacytic differentiation and amyloid deposition.

A 65-year-old woman with a resolved history of epilepsy due to a motor vehicle accident and hippocampal sclerosis presented with recurrent de novo seizures. Brain imaging demonstrated enhancement in the left parieto-occipital lobe. At histopathological examination, the lesion displayed a diffuse lymphoid infiltrate comprised of small atypical lymphocytes, plasmacytoid lymphocytes, and scattered plasma cells with amyloid deposition. Pathology workup demonstrated a monotypic B-cell phenotype of the lymphoid infiltrate, expressing lambda light chain restriction and plasmacytic differentiation without MYD88 mutations. The patient had no systemic evidence of lymphoma, plasma cell dyscrasia, or amyloidosis. A diagnosis of low-grade B-cell lymphoma of the central nervous system with plasmacytic differentiation and amyloid deposition was made.

Optimizing Neurology Inpatient Documentation: A Pilot Study of a Novel Discharge Documentation EHR Tool.

Background and Purpose: Clinical documentation of patient acuity is a major determinant of payer reimbursement. This project aimed to improve case mix index (CMI) by incorporating a novel electronic health record (EHR) discharge documentation tool into the inpatient general neurology service at the University of California, Los Angeles (UCLA) Medical Center. Methods: We used data from Vizient AMC Hospital: Risk Model Summary for Clinical Data Base (CBD) 2017 to create a discharge diagnosis documentation tool consisting of dropdown menus to better capture relevant secondary diagnoses and comorbidities. After implementation of this tool, we compared pre- (July 2017-June 2019) and post-intervention (July 2019-June 2021) time periods on mean expected length of stay (LOS) and mean CMI with two sample T-tests and the percentage of encounters classified as having Major Complications/Comorbidities (MCC), with Complication/Comorbidity (CC), and without CC/MCC with tests of proportions. Results: Mean CMI increased significantly from 1.2 pre-intervention to 1.4 post-intervention implementation (P < .01). There was a pattern of increased MCC percentages for "Bacterial infections," "Other Disorders of Nervous System", "Multiple Sclerosis," and "Nervous System Neoplasms" diagnosis related groups post-intervention. Conclusions: This pilot study describes the creation of an innovative EHR discharge diagnosis documentation tool in collaboration with neurology healthcare providers, the clinical documentation improvement team, and neuro-informaticists. This novel discharge diagnosis documentation tool demonstrates promise in increasing CMI, shifting diagnosis related groups to a greater proportion of those with MCC, and improving the quality of clinical documentation.

Monitoring cardiac and ascending aortic procedures.

Although cardiac and aortic operations have been successfully performed for more than 60 years, the risk of neurologic complications remains high. In particular, the rate of stroke with cardiac operations continues to be significant in the 1%-5% range. Similarly, the risk of stroke with aortic operations remains in the range of 7%-10% despite many years of improving techniques. Because of this persistently high risk, the use of intra-operative neurophysiologic monitoring (IONM) has the potential of improving outcomes. This chapter provides an overview of cardiac/aortic arch procedures from the neurophysiologic standpoint and discusses the roles of different monitoring modalities in detecting injury.

Fast Neuro: A Care Model to Expedite Access to Neurology Clinic.

Background and Objectives: We set out to improve outpatient neurology access while reducing patient volume in the emergency department (ED) for nonemergent neurologic complaints. Methods: We created a rapid access model, University of California Los Angeles (UCLA) Fast Neuro, for patients referred from affiliated EDs to outpatient neurology, enabling appointments within 1 week of referral. Rapid access appointments were also available to established neurology patients with urgent concerns. Fast Neuro was built to reduce nonemergent neurologic care in the ED, improve outpatient neurology access, and avoid use of inpatient neurology services for nonemergent consults. The volume of referrals and neurology consults from the ED and wait time from referral to appointment were measured. Surveys were conducted at 3 and 6 months to assess satisfaction with the model by all stakeholders. Results: From January 2019 through January 2021, 201 patients were referred to outpatient neurology through UCLA Fast Neuro. Wait time for an outpatient neurology appointment was reduced from the prior period by 82.5% (7.0 ± 5.5 vs 40 ± 4.1 days). The number of nonemergent consults from the ED was reduced by 60% (4.1 ± 1.9/mo vs 10.3 ± 1.7/mo). Surveys showed wide acceptance of the new model with 92% of attending physicians and advanced practice providers and 89% of residents endorsing that UCLA Fast Neuro patients did not detract from their clinic experience. Discussion: UCLA Fast Neuro improved ED throughput, reduced inpatient neurology consults from the ED, and decreased wait times for outpatient neurology appointments without using the inpatient neurology service for nonurgent consults. UCLA Fast Neuro was successful. Exploration of how to scale and implement the model of access more broadly is warranted.

Facial diplegia with paresthesia associated with anti-GD1a antibodies.

A 26-year-old previously healthy man presented with progressive facial diplegia and sensory deficits to pinprick in a stocking-glove distribution. Lumbar puncture revealed cytoalbuminologic dissociation, and a nerve conduction study of the right facial nerve demonstrated a proximal demyelinating process. He was started on intravenous immunoglobulin given concern for a Guillain-Barré syndrome variant, and his symptoms improved over several days. This case illustrates the clinical features of facial diplegia with paresthesias, a rare variant of Guillain-Barré syndrome. Unlike most reported cases of facial diplegia with paresthesias that have demonstrated positive anti-ganglioside M2 antibodies, this case is unique given the positivity of anti-ganglioside D1a IgG/IgM antibodies.

Safety of focused ultrasound neuromodulation in humans with temporal lobe epilepsy.

OBJECTIVE: Transcranial Focused Ultrasound (tFUS) is a promising new potential neuromodulation tool. However, the safety of tFUS neuromodulation has not yet been assessed adequately. Patients with refractory temporal lobe epilepsy electing to undergo an anterior temporal lobe resection present a unique opportunity to evaluate the safety and efficacy of tFUS neuromodulation. Histological changes in tissue after tFUS can be examined after surgical resection, while further potential safety concerns can be assessed using neuropsychological testing. METHODS: Neuropsychological functions were assessed in eight patients before and after focused ultrasound sonication of the temporal lobe at intensities up to 5760 mW/cm2. Using the BrainSonix Pulsar 1002, tFUS was delivered under MR guidance, using the Siemens Magnetom 3T Prisma scanner. Neuropsychological changes were assessed using various batteries. Histological changes were assessed using hematoxylin and eosin staining, among others. RESULTS: With respect to safety, the histological analysis did not reveal any detectable damage to the tissue, except for one subject for whom the histology findings were inconclusive. In addition, neuropsychological testing did not show any statistically significant changes in any test, except for a slight decrease in performance on one of the tests after tFUS. SIGNIFICANCE: This study supports the hypothesis that low-intensity Transcranial Focused Ultrasound (tFUS) used for neuromodulation of brain circuits at intensities up to 5760 mW/cm2 may be safe for use in human research. However, due to methodological limitations in this study and inconclusive findings, more work is warranted to establish the safety. Future directions include greater number of sonications as well as longer exposure at higher intensity levels to further assess the safety of tFUS for modulation of neuronal circuits.

Clinically indicated electrical stimulation strategies to treat patients with medically refractory epilepsy.

Focal epilepsies represent approximately half of all diagnoses, and more than one-third of these patients are refractory to pharmacologic treatment. Although resection can result in seizure freedom, many patients do not meet surgical criteria, as seizures may be multifocal in origin or have a focus in an eloquent region of the brain. For these individuals, several U.S. Food and Drug Administration (FDA)-approved electrical stimulation paradigms serve as alternative options, including vagus nerve stimulation, responsive neurostimulation, and stimulation of the anterior nucleus of the thalamus. All of these are safe, flexible, and lead to progressive seizure control over time when used as an adjunctive therapy to antiepileptic drugs. Focal epilepsies frequently involve significant comorbidities such as cognitive decline. Similar to antiepilepsy medications and surgical resection, current stimulation targets and parameters have yet to address cognitive impairments directly, with patients reporting persistent comorbidities associated with focal epilepsy despite a significant reduction in the number of their seizures. Although low-frequency theta oscillations of the septohippocampal network are critical for modulating cellular activity and, in turn, cognitive processing, the coordination of neural excitability is also imperative for preventing seizures. In this review, we summarize current FDA-approved electrical stimulation paradigms and propose that theta oscillations of the medial septal nucleus represent a novel neuromodulation target for concurrent seizure reduction and cognitive improvement in epilepsy. Ultimately, further advancements in clinical neurostimulation strategies will allow for the efficient treatment of both seizures and comorbidities, thereby improving overall quality of life for patients with epilepsy.

AR2, a novel automatic muscle artifact reduction software method for ictal EEG interpretation: Validation and comparison of performance with commercially available software.

Objective: To develop a novel software method (AR2) for reducing muscle contamination of ictal scalp electroencephalogram (EEG), and validate this method on the basis of its performance in comparison to a commercially available software method (AR1) to accurately depict seizure-onset location. Methods: A blinded investigation used 23 EEG recordings of seizures from 8 patients. Each recording was uninterpretable with digital filtering because of muscle artifact and processed using AR1 and AR2 and reviewed by 26 EEG specialists. EEG readers assessed seizure-onset time, lateralization, and region, and specified confidence for each determination. The two methods were validated on the basis of the number of readers able to render assignments, confidence, the intra-class correlation (ICC), and agreement with other clinical findings. Results: Among the 23 seizures, two-thirds of the readers were able to delineate seizure-onset time in 10 of 23 using AR1, and 15 of 23 using AR2 (p<0.01). Fewer readers could lateralize seizure-onset (p<0.05). The confidence measures of the assignments were low (probable-unlikely), but increased using AR2 (p<0.05). The ICC for identifying the time of seizure-onset was 0.15 (95% confidence interval (CI), 0.11-0.18) using AR1 and 0.26 (95% CI 0.21-0.30) using AR2.  The EEG interpretations were often consistent with behavioral, neurophysiological, and neuro-radiological findings, with left sided assignments correct in 95.9% (CI 85.7-98.9%, n=4) of cases using AR2, and 91.9% (77.0-97.5%) (n=4) of cases using AR1. Conclusions: EEG artifact reduction methods for localizing seizure-onset does not result in high rates of interpretability, reader confidence, and inter-reader agreement. However, the assignments by groups of readers are often congruent with other clinical data. Utilization of the AR2 software method may improve the validity of ictal EEG artifact reduction.

Comparison of electromyographic (EMG) activity of selected forearm muscles during low grade resistance therapeutic exercises in individuals diagnosed with lateral epicondylitis.

BACKGROUND AND PURPOSE: This was a descriptive and exploratory study of electromyographic (EMG) activity of wrist extensor musculature specific to the extensor digitorum (ED), extensor carpi radialis brevis (ECRB) and flexor carpi radialis (FCR) in individuals with a medical diagnosis of the common work associated complaint of lateral epicondylitis (LE). The purpose was to evaluate and compare the EMG activity of the selected forearm muscles during three different types of resistive (strengthening) therapeutic exercises (rubber ball, theraputty, and "make-it-disappear" (MID) sponge) in participants with LE. PARTICIPANTS: Five individuals between the ages of 44 and 55 years of age diagnosed with lateral epicondylitis by a physician were recruited on a voluntary basis from a local outpatient clinic. METHODS: The participants completed 1 min. of each of the resistive exercises, which were assigned randomly. Muscle activity was collected simultaneously by 3 surface electrodes (4/18/16 DE-2.3 silver surface EMG electrodes, Delsys Inc, Boston, MA) and recorded on an EMG Myomonitor-4 (Delsys Inc, Boston, MA) utilizing EmgCE software (Delsys Inc, Boston, MA). The raw EMG signal was converted to a root mean square (RMS) at each 0.0625 second interval during the full 60 second recording using EMGWorks, (Delsys, Inc, Boston, MA). The data were pooled, and the mean RMS was then determined as an overall measure of activity for each muscle during the 60 recording. RESULTS: A 1-way ANOVA with Tukey's post-test was completed using Prizm Software (Graph Pad Software, Inc, San Diego, CA) for a comparison of the mean RMS values of each muscle during each activity. Statistically significant between group differences were noted for all muscles, among all exercises. Relative activity was noted to be greatest for ED and FCR during MID exercise, and for ECRB during putty exercise. CONCLUSION: All three exercises represent different patterns of muscle activity, for the muscles observed. The possible differences in the recorded activity may be consequent to the specific positioning and movement requirements involved in the performance of the distinct exercises. Practitioners may find the evidence of this study helpful in designing rehabilitation programs for those affected with lateral epicondylitis.

Successful treatment of refractory simple motor status epilepticus with lacosamide and levetiracetam.

Lacosamide has been reported to have been successfully used for non-convulsive status epilepticus after benzodiazepine failure, and convulsive status epilepticus after benzodiazepine and levetiracetam failure. We report a case of simple motor status epilepticus refractory to benzodiazepines and multiple anti-epileptic medications (AEDs) over 4 days. The addition of lacosamide in combination with existing levetiracetam aborted the continuous seizure with maintenance of seizure freedom through the most recent follow-up at 4 weeks.

Effective mast cell degranulating peptide inhibitors of the IgE/Fc epsilonRI receptor interaction.

Previous studies with mast cell degranulating (MCD) peptide have shown that peptide [Ala(12)]MCD 8 was an inhibitor of IgE binding to mast cell receptors. In an attempt to produce increased inhibition, analogs were synthesized that maintained the alanine residue in position 12 in the MCD peptide sequence and were further modified at both termini. Analogs modified at the C-terminus were [Ala(12),desLys(21)]MCD 2 and [Ala(12),D-Lys(21)]MCD 4. N-terminus modifications were [desLys(6)-Arg(7)-His(8),Ala(12)]MCD 1, [Ala(6), Ala(12)]MCD 6, and [Val(6),Ala(12)]MCD 7. To assess the role of the Proline(12), analogs [D-Ala(12)]MCD 3 and [Meleu(12)]MCD 5 were also synthesized. The analogs were tested for binding to the IgE receptor in cultured mast cells. Inhibitory activity of IgE-caused degranulation was measured using a beta-hexosaminidase assay. Circular dichroism (CD) and molecular modeling of selected analogs were used to follow possible structural differences among these analogs. All analogs showed binding affinity to the IgE receptor and inhibition of IgE-induced mast cell degranulation at different levels. Differences in inhibition were most likely because of diverse interactions of the analogs with the receptor as inferred by the CD and modeling studies. Based on the results of the beta-hexosaminidase assay, analog [Val(6), Ala(12)]MCD 7 proved to be an excellent inhibitor of IgE-mediated mast cell degranulation.

Mechanism of PLC-mediated Kir3 current inhibition.

A large number of ion channels maintain their activity through direct interactions with phosphatidylinositol bisphosphate (PIP2). For such channels, hydrolysis of PIP2 causes current inhibition. It has become controversial whether the inhibitory effects on channel activity represent direct effects of PIP2 hydrolysis or of downstream PKC action. We studied Phospholipase C (PLC)-dependent inhibition of G protein-activated inwardly rectifying K+ (Kir3) channels. By monitoring simultaneously channel activity and PIP2 hydrolysis, we determined that both direct PIP2 depletion and PKC actions contribute to Kir3 current inhibition. We show that the PKC-induced effects strongly depend on PIP2 levels in the membrane. At the same time, we show that PKC destabilizes Kir3/PIP2 interactions and enhances the effects of PIP2 depletion on channel activity. These results demonstrate that PIP2 depletion and PKC-mediated effects reinforce each other and suggest that both of these interdependent mechanisms contribute to Kir3 current inhibition. This mechanistic insight may explain how even minor changes in PIP2 levels can have profound effects on Kir3 activity. We also show that stabilization of Kir3/PIP2 interactions by Gbetagamma attenuates both PKC and Gq-mediated current inhibition, suggesting that diverse pathways regulate Kir3 activity through modulation of channel interactions with PIP2.

Protein kinase A modulates PLC-dependent regulation and PIP2-sensitivity of K+ channels.

Neurotransmitter and hormone regulation of cellular function can result from a concomitant stimulation of different signaling pathways. Signaling cascades are strongly regulated during disease and are often targeted by commonly used drugs. Crosstalk of different signaling pathways can have profound effects on the regulation of cell excitability. Members of all the three main structural families of potassium channels: inward-rectifiers, voltage-gated and 2-P domain, have been shown to be regulated by direct phosphorylation and Gq-coupled receptor activation. Here we test members of each of the three families, Kir3.1/Kir3.4, KCNQ1/KCNE1 and TREK-1 channels, all of which have been shown to be regulated directly by phosphatidylinositol bisphosphate (PIP2). The three channels are inhibited by activation of Gq-coupled receptors and are differentially regulated by protein kinase A (PKA). We show that Gq-coupled receptor regulation can be physiologically modulated directly through specific channel phosphorylation sites. Our results suggest that PKA phosphorylation of these channels affects Gq-coupled receptor inhibition through modulation of the channel sensitivity to PIP2.

Cyclin D1 overexpression and response to bortezomib treatment in a breast cancer model.

BACKGROUND: Cyclin D1 is frequently overexpressed in breast cancer, and its overexpression is, surprisingly, associated with improved survival. One potential mechanism for this association involves signal transducer and activator of transcription 3 (STAT3). METHODS: Cyclin D1 and STAT3 expression were assessed in human tumors using microarray analysis and in breast cancer cell lines HBL100, T47D, MCF7, MDA-MB-453, and BT20 and in HBL100 and T47D cells stably overexpressing cyclin D1 using immunoblot analysis. Cyclin D1 protein was stabilized by treatment with the proteasome inhibitor bortezomib, and the effects on STAT3 expression in vitro was determined by using immunoblotting and on xenograft tumor growth and apoptosis in vivo was determined by using terminal deoxyuridine nick-end labeling assays. All statistical tests were two-sided. RESULTS: Tumors with high cyclin D1 expression (n = 17) had low STAT3 expression (mean = 274 arbitrary units), and those with low cyclin D1 expression (n = 31) had high STAT3 expression (mean = 882 arbitrary units) (P<.001). In HBL100 and T47D parental and cyclin D1-overexpressing cells, cyclin D1 overexpression was also inversely associated with STAT3 expression, and cyclin D1 directly reduced the expression of STAT3. Stabilization of cyclin D1 protein by bortezomib treatment further amplified the cyclin D1-dependent repression of STAT3 in vitro and slowed tumor growth in vivo (week 7: untreated mean = 185.7 mm3 versus treated mean = 136.2 mm3, difference = 49.5 mm3, 95% confidence interval [CI] = 18 to 81 mm3, P = .007; week 8: untreated mean = 240.2 mm3 versus treated mean = 157.3 mm3, difference = 82.9 mm3, 95% CI = 9.1 to 156.7 mm3, P = .0014; and week 9: untreated mean = 256.4 mm3 versus treated mean = 170.2 mm3, difference = 86.2 mm3, 95% CI = 22.8 to 149.6 mm3, P = .006) and increased apoptosis (untreated mean = 19% versus treated mean = 54%, difference = 35%, 95% CI = 24.7% to 45.4%; P = .013) of xenograft tumors. CONCLUSIONS: Cyclin D1 repression of STAT3 expression may explain the association between cyclin D1 overexpression and improved outcome in breast cancer. In addition, bortezomib can amplify the proapoptotic function of cyclin D1, raising the possibility that cyclin D1 levels may be a marker for predicting the response to this novel drug.