Faculty Bibliography

BACKGROUND:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the causative agent of coronavirus disease 2019 (COVID-19), may lead to severe systemic inflammatory response, pulmonary damage, and even acute respiratory distress syndrome (ARDS). This in turn may result in respiratory failure and in death. Experimentally, acetylcholine (ACh) modulates the acute inflammatory response, a neuro-immune mechanism known as the inflammatory reflex. Recent clinical evidence suggest that electrical and chemical stimulation of the inflammatory reflex may reduce the burden of inflammation in chronic inflammatory diseases. Pyridostigmine (PDG), an ACh-esterase inhibitor (i-ACh-e), increases the half-life of endogenous ACh, therefore mimicking the inflammatory reflex. This clinical trial is aimed at evaluating if add-on of PDG leads to a decrease of invasive mechanical ventilation and death among patients with severe COVID-19. METHODS:A parallel-group, multicenter, randomized, double-blinded, placebo-controlled, phase 2/3 clinical trial to test the efficacy of pyridostigmine bromide 60 mg/day P.O. to reduce the need for invasive mechanical ventilation and mortality in hospitalized patients with severe COVID-19. DISCUSSION/CONCLUSIONS:This study will provide preliminary evidence of whether or not -by decreasing systemic inflammation- add-on PDG can improve clinical outcomes in patients with severe COVID-19. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov NCT04343963 (registered on April 14, 2020).

The ongoing global pandemic (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a huge public health issue. Hence, we devised a multiplex reverse transcription loop-mediated isothermal amplification (mRT-LAMP) coupled with a nanoparticle-based lateral flow biosensor (LFB) assay (mRT-LAMP-LFB) for diagnosing COVID-19. Using two LAMP primer sets, the ORF1ab (opening reading frame 1a/b) and N (nucleoprotein) genes of SARS-CoV-2 were simultaneously amplified in a single-tube reaction, and detected with the diagnosis results easily interpreted by LFB. In presence of FITC (fluorescein)-/digoxin- and biotin-labeled primers, mRT-LAMP produced numerous FITC-/digoxin- and biotin-attached duplex amplicons, which were determined by LFB through immunoreactions (FITC/digoxin on the duplex and anti-FITC/digoxin on the test line of LFB) and biotin/treptavidin interaction (biotin on the duplex and strptavidin on the polymerase nanoparticle). The accumulation of nanoparticles leaded a characteristic crimson band, enabling multiplex analysis of ORF1ab and N gene without instrumentation. The limit of detection (LoD) of COVID-19 mRT-LAMP-LFB was 12 copies (for each detection target) per reaction, and no cross-reactivity was generated from non-SARS-CoV-2 templates. The analytical sensitivity of SARS-CoV-2 was 100% (33/33 oropharynx swab samples collected from COVID-19 patients), and the assay's specificity was also 100% (96/96 oropharynx swab samples collected from non-COVID-19 patients). The total diagnostic test can be completed within 1 h from sample collection to result interpretation. In sum, the COVID-19 mRT-LAMP-LFB assay is a promising tool for diagnosing SARS-CoV-2 infections in frontline public health field and clinical laboratories, especially from resource-poor regions.

BACKGROUND:Activation of the mammalian target of rapamycin (mTOR) pathway is observed in neurofibromatosis type 1 (NF1) associated low-grade gliomas (LGGs), but agents that inhibit this pathway, including mTOR inhibitors, have not been studied in this population. We evaluate the efficacy of the orally administered mTOR inhibitor everolimus for radiographically progressive NF1-associated pediatric LGGs. METHODS:Children with radiologic-progressive, NF1-associated LGG and prior treatment with a carboplatin-containing chemotherapy were prospectively enrolled on this phase II clinical trial to receive daily everolimus. Whole blood was analyzed for everolimus and markers of phosphatidylinositol-3 kinase (PI3K)/mTOR pathway inhibition. Serial MRIs were obtained during treatment. The primary endpoint was progression-free survival at 48 weeks. RESULTS:Twenty-three participants (median age, 9.4 y; range, 3.2-21.6 y) were enrolled. All participants were initially evaluable for response; 1 patient was removed from study after development of a malignant peripheral nerve sheath tumor. Fifteen of 22 participants (68%) demonstrated a response, defined as either shrinkage (1 complete response, 2 partial response) or arrest of tumor growth (12 stable disease). Of these, 10/15 remained free of progression (median follow-up, 33 mo). All remaining 22 participants were alive at completion of therapy. Treatment was well tolerated; no patient discontinued therapy due to toxicity. Pharmacokinetic parameters and pre-dose concentrations showed substantial between-subject variability. PI3K/mTOR pathway inhibition markers demonstrating blood mononuclear cell mTOR pathway inactivation was achieved in most participants. CONCLUSION/CONCLUSIONS:Individuals with recurrent/progressive NF1-associated LGG demonstrate significant disease stability/shrinkage during treatment with oral everolimus with a well-tolerated toxicity profile. Everolimus is well suited for future consideration as upfront or combination therapy in this patient population.

OBJECTIVE:Autism spectrum disorder (ASD) is a neurodevelopmental disorder frequently associated with epilepsy and epilepsy is a leading cause of death in ASD patients. Despite growing interest in genetic, neurophysiological and clinical overlaps, data on ictal electroencephalographic (EEG) recordings in ASD are lacking since behavioral disorders often make it difficult to obtain EEG recordings. We examined ictal EEG features in a consecutive series of patients with ASD and epilepsy. METHODS:We retrospectively identified 400 consecutive patients with ASD and epilepsy at our Level 4 Epilepsy center between 2015 and 2019; 45 had at least one EEG-recorded seizure captured. Demographics, age of nonfebrile seizure onset, age of ASD diagnosis, language, magnetic resonance imagining findings, genetic testing and EEG studies were reviewed. Seizures were classified by semiologic and electrographic features. Ictal findings were analyzed. RESULTS:A total of 497 seizures were captured in 45 patients: 20 patients with focal onset epilepsy had 126 seizures (median: 1, range: 1-30), 17 patients with generalized onset epilepsy had 88 seizures (median: 2, range: 1-15), 7 patients with Lennox-Gastaut syndrome had 270 seizures (median: 12, range: 1-74) and one patient had both right hemisphere focal and generalized onsets (12 focal, 1 generalized). SIGNIFICANCE/CONCLUSIONS:Our study is the first to analyze a large set of ictal data in patients with autism spectrum disorder, a population traditionally difficult to obtain ictal recordings. Our results confirm the diverse spectrum of seizure types and provide clinical-EEG correlates of seizures in ASD patients. Both focal-onset and generalized-onset seizures were recorded, confirming that ASD patients have higher rates of both focal and generalized epilepsy syndromes. Among patients with focal epilepsy, temporal and frontal onsets were frequent, suggesting the possibility of epilepsy surgery or brain stimulation. EEG to classify seizures and epilepsies is critical to determine therapeutic options and effort should be made to obtain EEGs in this heterogenous population.

BACKGROUND:Paroxysmal symptoms (PS), defined as short-lasting, recurrent, and stereotyped neurological symptoms, are frequently reported by patients with Neuromyelitis Optica Spectrum Disorder (NMOSD). Their prevalence and spectrum of presentations in NMOSD have not been fully characterized. METHODS:Patients with NMOSD, who were members of a closed international Facebook Group, were recruited to complete an anonymous survey on REDCap. Participants were queried regarding demographic and NMOSD-related characteristics and PS history. RESULTS:The sample consisted of 219 responders with self-reported NMOSD, of whom 134 (63.8%) reported testing positive for AQP4 Antibody. 156 responders (71.9%) reported ≥1 type of PS during the disease course. The most common PS were intermittent tingling/numbness sensation (N=106, 67.9%), followed by involuntary muscle contractions/abnormal posture (N=95, 60.9%), hot/cold/burning sensations (N=87, 55.8%), and shock-like sensations along the spine or limbs (N=77, 49.4%). 150 responders (96% of those with PS) reported that PS were painful; in 82 responders (54.6%), the pain intensity reached ≥ 8/10 and in 40 responders (26.0%) - 10/10 level. PS were most commonly aggravated by fatigue (105 responders, 70.0%), physical activity (N=86, 57.3%), and neck flexion (N=39 responders, 26.0%). 82 patients (52.5% of those with PS) reported having been prescribed one or more medications for PS. Less than 50% reported them to be 'very helpful.' CONCLUSIONS:This survey highlights that PS occurs commonly in NMOSD patients. The symptomatology of PS is diverse. PS are often painful and not adequately treated. Our study represents a novel method to learn more about a rare disease from the patient's perspective. Given the fact that the study was conducted using an anonymous questionnaire and the diagnosis of NMOSD was self-reported by the survey participants, its' results should be regarded as a first step towards the understanding of PS in NMOSD, which should be further validated in a larger, controlled study.

A 38-year-old male presented with a three-week history of bilateral lower extremity choreiform movements. History included sleep abnormalities, rushed and unintelligible speech, with delusions two to six months prior to presentation. He also developed mild dysphagia, staring spells, and anterograde amnesia. On examination, he had pressured speech, asynchronous cycling movements of the bilateral lower extremities persisting during sleep, occasional ballistic movements of the upper extremities, and ataxia. Magnetic resonance imaging (MRI) of the brain showed high cortical signal change in bilateral parieto-occipital cortices with evidence of medullary olive hypertrophy bilaterally. Electroencephalography showed generalized slowing without periodic spikes. Cerebrospinal fluid was positive for protein 14-3-3 and real-time quaking-induced conversion. Genetic testing was positive for autosomal dominant prion protein gene (PRNP) genetic mutation. The patient passed away three months after discharge. This case provides previously undescribed imaging and movement abnormalities in a patient with familial Creutzfeldt-Jakob disease (CJD), and suggests that CJD should not be removed from the differential in patients with these atypical findings.

BACKGROUND AND PURPOSE/OBJECTIVE:Anticoagulation therapy not only reduces the risk of ischemic stroke in atrial fibrillation (AF) but also predisposes patients to hemorrhagic complications. There is limited knowledge on the risk of first-ever ischemic stroke in patients with AF after extracranial hemorrhage (ECH). METHODS:-VASc score, or the presence/absence of a gastrointestinal or genitourinary cancer. RESULTS:We identified 764 257 patients with AF (mean age 75 years, 49% women) without a documented history of stroke. Of these, 98 647 (13%) had an ECH-associated hospitalization, and 22 748 patients (3%) developed an ischemic stroke during the study period. Compared to patients without ECH, subjects with ECH had ≈15% higher rate of ischemic stroke (overall adjusted hazard ratio, 1.15 [95% CI, 1.11-1.19]). The risk appeared to remain elevated for at least 18 months after the index ECH. In subgroup analyses, the risk was highest in subjects with a primary admission diagnosis of ECH, severe ECH, gastrointestinal-type ECH, with gastrointestinal or genitourinary cancer, and age ≥60 years. CONCLUSIONS:Patients with AF hospitalized with ECH may have a slightly elevated risk for future ischemic stroke. Particular consideration should be given to the optimal balance between the benefits and risks of anticoagulation therapy and the use of nonanticoagulant alternatives, such as left atrial appendage closure in this vulnerable population.

BACKGROUND:Subthalamic (STN) and pallidal (GPi) deep brain stimulation (DBS) improve quality of life, motor, and nonmotor symptoms (NMS) in advanced Parkinson's disease (PD). However, few studies have compared their nonmotor effects. OBJECTIVE:To compare nonmotor effects of STN-DBS and GPi-DBS. METHODS:In this prospective, observational, multicenter study including 60 PD patients undergoing bilateral STN-DBS (n = 40) or GPi-DBS (n = 20), we examined PDQuestionnaire (PDQ), NMSScale (NMSS), Unified PD Rating Scale-activities of daily living, -motor impairment, -complications (UPDRS-II, -III, -IV), Hoehn&Yahr, Schwab&England Scale, and levodopa-equivalent daily dose (LEDD) preoperatively and at 6-month follow-up. Intra-group changes at follow-up were analyzed with Wilcoxon signed-rank or paired t-test, if parametric tests were applicable, and corrected for multiple comparisons. Inter-group differences were explored with Mann-Whitney-U/unpaired t-tests. Analyses were performed before and after propensity score matching which balanced out demographic and preoperative clinical characteristics. Strength of clinical changes was assessed with effect size. RESULTS:In both groups, PDQ, UPDRS-II, -IV, Schwab&England Scale, and NMSS improved significantly at follow-up. STN-DBS was significantly better for LEDD reduction, GPi-DBS for UPDRS-IV. While NMSS total score outcomes were similar, explorative NMSS domain analyses revealed distinct profiles: Both targets improved sleep/fatigue and mood/cognition, but only STN-DBS the miscellaneous (pain/olfaction) and attention/memory and only GPi-DBS cardiovascular and sexual function domains. CONCLUSIONS:To our knowledge, this is the first study to report distinct patterns of beneficial nonmotor effects of STN-DBS and GPi-DBS in PD. This study highlights the importance of NMS assessments to tailor DBS target choices to patients' individual motor and nonmotor profiles.