Faculty Bibliography

OBJECTIVE:The current Phase 2b study aimed to evaluate the efficacy of mindfulness-based cognitive therapy for migraine (MBCT-M) to reduce migraine-related disability in people with migraine. BACKGROUND:Mindfulness-based interventions represent a promising avenue to investigate effects in people with migraine. MBCT teaches mindfulness meditation and cognitive-behavioral skills and directly applies these skills to address disease-related cognitions. METHODS:Participants with migraine (6-30 headache days/month) were recruited from neurology office referrals and local and online advertisements in the broader New York City area. During the 30-day baseline period, all participants completed a daily headache diary. Participants who met inclusion and exclusion criteria were randomized in a parallel design, stratified by chronic migraine status, to receive either 8 weekly individual MBCT-M sessions or 8 weeks of waitlist/treatment as usual (WL/TAU). All participants completed surveys including primary outcome evaluations at Months 0, 1, 2, and 4. All participants completed a headache diary during the 30-day posttreatment evaluation period. Primary outcomes were the change from Month 0 to Month 4 in the headache disability inventory (HDI) and the Migraine Disability Assessment (MIDAS) (total score ≥ 21 indicating severe disability); secondary outcomes (headache days/30 days, average headache attack pain intensity, and attack-level migraine-related disability [Migraine Disability Index (MIDI)]) were derived from the daily headache diary. RESULTS:Sixty participants were randomized to receive MBCT-M (n = 31) or WL/TAU (n = 29). Participants (M age = 40.1, SD = 11.7) were predominantly White (n = 49/60; 81.7%) and Non-Hispanic (N = 50/60; 83.3%) women (n = 55/60; 91.7%) with a graduate degree (n = 35/60; 55.0%) who were working full-time (n = 38/60; 63.3%). At baseline, the average HDI score (51.4, SD = 19.0) indicated a moderate level of disability and the majority of participants (50/60, 83.3%) fell in the "Severe Disability" range in the MIDAS. Participants recorded an average of 16.0 (SD = 5.9) headache days/30 days, with an average headache attack pain intensity of 1.7 on a 4-point scale (SD = 0.3), indicating moderate intensity. Average levels of daily disability reported on the MIDI were 3.1/10 (SD = 1.8). For the HDI, mean scores decreased more from Month 0 to Month 4 in the MBCT-M group (-14.3) than the waitlist/treatment as an usual group (-0.2; P < .001). For the MIDAS, the group*month interaction was not significant when accounting for the divided alpha, P = .027; across all participants in both groups, the estimated proportion of participants falling in the "Severe Disability" category fell significantly from 88.3% at Month 0 to 66.7% at Month 4, P < .001. For diary-reported headache days/30 days an average headache attack pain intensity, neither the group*month interaction (Ps = .773 and .888, respectively) nor the time effect (Ps = .059 and .428, respectively) was significant. Mean MIDI scores decreased in the MBCT-M group (-0.6/10), whereas they increased in the waitlist/treatment as an usual group (+0.3/10), P = .007. CONCLUSIONS:MBCT-M demonstrated efficacy to reduce headache-related disability and attack-level migraine-related disability. MBCT-M is a promising emerging treatment for addressing migraine-related disability.

Background: Quantitative measurement of serum markers play an important role in the diagnosis and treatment monitoring of hepatitis b virus (HBV) infection. In the present study, we analyzed the data from Abbott Architect i2000 immunoassay analyzer and investigate the relationship between HBeAg and anti-HBe.
Method(s): Quantitative data of HBV serum markers between January first 2013 and March twentyeight 2016, which are measured by Abbott Architect i2000, were exported from laboratory information system. Data cleaning and analysis were performed by R language. Records contain unprecise value were omitted and the rest were divided into groups according to the HBeAg state. The relationship between HBeAg and anti-HBe was explored by plotting and linear regression.
Result(s): Anti-HBe was correlated with HBeAg and linear regression showed R² equal to 0.92. Only in HBeAg positive data could this correlation be observed, whereas no pattern was observed from HBeAg negative ones. HBeAg and anti-HBe double positive can onley be seen in low HBeAg samples.
Conclusion(s): This study suggests that HBeAg partly interfere with the measurement of anti-HBe, which could lead to unprecise results of the patients who are HBeAg and anti-HBe double positive

The role of Varicella zoster virus (VZV) in neurological illness, particularly cerebrovascular disease, has been increasingly recognized. Primary infection by VZV causes varicella (chickenpox), after which the virus remains latent in neuronal ganglia. Later, during aging or immunosuppression, the virus can reactivate causing zoster (shingles). Virus reactivation can also spread to cerebral arteries causing vasculitis and stroke. Zoster is a recognized risk factor for stroke, but stroke can occur without preceding zoster rash. The diagnosis of VZV cerebral vasculitis is established by abnormal brain imaging and confirmed by presence of viral DNA or anti-VZV antibodies in cerebrospinal fluid. Treatment with acyclovir with or without prednisone is usually recommended. VZV vasculitis is a unique and uncommon stroke mechanism that has been under recognized. Careful diagnostic investigation may be warranted in a subgroup of patients with ischemic stroke to detect VZV vasculitis and initiate appropriate therapy. In the following review, we detail the clinical presentation of VZV vasculitis, diagnostic challenges in VZV detection, and suggest the ways to enhance recognition and treatment of this uncommon disease.

BACKGROUND:Deep brain stimulation (DBS) can be an effective therapy for tics and comorbidities in select cases of severe, treatment-refractory Tourette syndrome (TS). Clinical responses remain variable across patients, which may be attributed to differences in the location of the neuroanatomical regions being stimulated. We evaluated active contact locations and regions of stimulation across a large cohort of patients with TS in an effort to guide future targeting. METHODS:We collected retrospective clinical data and imaging from 13 international sites on 123 patients. We assessed the effects of DBS over time in 110 patients who were implanted in the centromedial (CM) thalamus (n=51), globus pallidus internus (GPi) (n=47), nucleus accumbens/anterior limb of the internal capsule (n=4) or a combination of targets (n=8). Contact locations (n=70 patients) and volumes of tissue activated (n=63 patients) were coregistered to create probabilistic stimulation atlases. RESULTS:Tics and obsessive-compulsive behaviour (OCB) significantly improved over time (p<0.01), and there were no significant differences across brain targets (p>0.05). The median time was 13 months to reach a 40% improvement in tics, and there were no significant differences across targets (p=0.84), presence of OCB (p=0.09) or age at implantation (p=0.08). Active contacts were generally clustered near the target nuclei, with some variability that may reflect differences in targeting protocols, lead models and contact configurations. There were regions within and surrounding GPi and CM thalamus that improved tics for some patients but were ineffective for others. Regions within, superior or medial to GPi were associated with a greater improvement in OCB than regions inferior to GPi. CONCLUSION/CONCLUSIONS:The results collectively indicate that DBS may improve tics and OCB, the effects may develop over several months, and stimulation locations relative to structural anatomy alone may not predict response. This study was the first to visualise and evaluate the regions of stimulation across a large cohort of patients with TS to generate new hypotheses about potential targets for improving tics and comorbidities.

PURPOSE OF REVIEW/OBJECTIVE:This article provides an overview of nystagmus and saccadic intrusions with the goal of facilitating recognition and differentiation of abnormal eye movements to assist with accurate diagnosis of neurologic disease and evidence-based specific treatment of oscillopsia. Myriad advances have been made in the understanding of several types of nystagmus and saccadic intrusions, even in the past 5 to 10 years, especially regarding underlying pathophysiology, leading to pharmacologic advances rooted in physiologic principles. RECENT FINDINGS/RESULTS:Specific recent advances in the study of nystagmus and saccadic intrusions include (1) improved understanding of the underlying etiologies and mechanisms of nystagmus enhanced or unmasked by provocative maneuvers such as supine position or head shaking; (2) recognition of the differences in behavior and treatment responsivity of acquired pendular nystagmus in demyelinating disease versus oculopalatal myoclonus; (3) recognition that oculopalatal myoclonus results from a dual mechanism of abnormal inferior olivary gap junction connection formation and maladaptive cerebellar learning; and (4) well-controlled clinical trials to evaluate the efficacy of pharmacologic interventions, such as memantine for acquired pendular nystagmus and 4-aminopyridine for downbeat nystagmus. SUMMARY/CONCLUSIONS:Accurate recognition of nystagmus and saccadic intrusions, including familiarity with the subtleties of examination techniques that allow such eye movements to be unmasked, is critical to proper diagnosis and ultimate alleviation of the visual impairment these patients experience.

BACKGROUND:H3 K27M-mutant diffuse midline glioma is a fatal malignancy with no proven medical therapies. The entity predominantly occurs in children and young adults. ONC201 is a small molecule selective antagonist of dopamine receptor D2/3 (DRD2/3) with an exceptional safety profile. Following up on a durable response in the first H3 K27M-mutant diffuse midline glioma patient who received ONC201 (NCT02525692), an expanded access program was initiated. METHODS:Patients with H3 K27M-mutant gliomas who received at least prior radiation were eligible. Patients with leptomeningeal spread were excluded. All patients received open-label ONC201 orally once every week. Safety, radiographic assessments, and overall survival were regularly assessed at least every 8 weeks by investigators. As of August 2018, a total of 18 patients with H3 K27M-mutant diffuse midline glioma or DIPG were enrolled to single patient expanded access ONC201 protocols. Among the 18 patients: seven adult (> 20 years old) and seven pediatric (< 20 years old) patients initiated ONC201 with recurrent disease and four pediatric patients initiated ONC201 following radiation, but prior to disease recurrence. FINDINGS/RESULTS:Among the 14 patients with recurrent disease prior to initiation of ONC201, median progression-free survival is 14 weeks and median overall survival is 17 weeks. Three adults among the 14 recurrent patients remain on treatment progression-free with a median follow up of 49.6 (range 41-76.1) weeks. Among the 4 pediatric patients who initiated adjuvant ONC201 following radiation, two DIPG patients remain progression-free for at least 53 and 81 weeks. Radiographic regressions, including a complete response, were reported by investigators in a subset of patients with thalamic and pontine gliomas, along with improvements in disease-associated neurological symptoms. INTERPRETATION/CONCLUSIONS:The clinical outcomes and radiographic responses in these patients provide the preliminary, and initial clinical proof-of-concept for targeting H3 K27M-mutant diffuse midline glioma with ONC201, regardless of age or location, providing rationale for robust clinical testing of the agent.

INTRODUCTION: Familial dysautonomia (FD) is a progressive neurogenetic disease with carrier rate as high as 1 in 18 persons in European Jews of Polish origin. Clinical hallmarks include cardiovascular instability, spinal deformities, renal dysfunction, alacrima, ataxia, and impaired nociception. Physical or emotional stress may elicit autonomic crises characterized by hypertension and vomiting. Despite profound sensory deficits, GI perturbations are frequently reported by FD patients. While the incidence of inflammatory bowel disease (IBD) and FD is unknown, concurrence is underreported given increased frequency of both diseases in Ashkenazi Jews. CASE DESCRIPTION/METHODS: We report a 33-year-old female with FD and ulcerative colitis who presented with one week of abdominal pain and bloody diarrhea. She had been maintained on balsalazide. Colonoscopy one year prior revealed endoscopic and histologic remission. On physical examination, her abdomen was tender in the lower quadrants. A CT scan revealed pancolitis. Stool studies resulted negative. Her CRP was 58.4 mg/L and albumin was 2.4 g/dL. A flexible sigmoidoscopy noted Mayo endoscopic score 3 in the rectum and CMV staining was negative. The patient was started on IV steroids. Her hospital course was complicated by ileus, parainfluenza infection, and MSSA bacteremia with a pacemaker lead vegetation, requiring extraction. Lack of optimal clinical response to treatment on hospital day five led to consideration of alternative treatments with careful attention to her underlying FD. A subtotal colectomy with end ileostomy was unfavorable due to concern for volume loss. Infliximab and cyclosporine were opposed due to infection risk and later exhibiting possible nephrotoxicity. During this discussion the patient improved enough to be transitioned to oral steroids with a plan to initiate vedolizumab as an outpatient. On recent colonoscopy she had achieved mucosal healing. DISCUSSION: This is the first case of UC in a FD patient reported. Given myriad GI symptoms in the later diagnosis it can be hard to distinguish disease-related from treatment-related events. Due to the gut-specificity of vedolizumab, infection risk is considerably reduced compared to that of other biologics and is the most favorable option in the setting of underlying FD. This case highlights the difficulty encountered when treating IBD in the setting of systemic illness and underscores the need to carefully consider management options to enhance patient outcomes. (Figure Presented)

Background. CRAb is a major cause of healthcare-associated infections and is associated with high mortality due to the lack of reliable treatment options. We aimed to elucidate the contemporary population structure of CRAb isolates circulating in US hospitals using whole-genome sequencing (WGS). Methods. A total of 131 CRAb isolates were identified at four tertiary care medical centers located in Ohio, Pennsylvania, Texas and North Carolina between 2017 and 2018. The genomes were sequenced with Illumina NextSeq and De novo assembled. Sequence types (STs) were identified using the Pasteur Institute MLST scheme. beta-Lactamase genes were identified by ResFinder and manually curated. Results. The 131 isolates belonged to 10 different ST types, including 8 known and 2 novel ones. In this collection, 101 isolates (77.1%) belonged to ST2, the dominant drug-resistant clone in the United States and Europe; 20 isolates belonged to ST499, a less common, but also globally distributed clone. Two isolates each belonged to ST46 and ST79, both common in South America. For the chromosomally encoded blaOXA-51-group genes, 11 variants were identified with blaOXA-66, blaOXA-82, and blaOXA-95 being predominant. For the chromosomally encoded blaADC-group genes, 26 variants were identified, with blaADC-161, blaADC-181, and blaADC-30 being the most common. The most frequent acquired carbapenemase gene was blaOXA-23, which was present in 89 isolates (67.9%). Other acquired blaOXA carbapenemase genes were identified much less frequently and included blaOXA-24, blaOXA-72, blaOXA-207, and blaOXA-237. 17 isolates (13.0%) did not contain any known acquired carbapenemase genes despite resistance to carbapenems. Conclusion. ST2 is the most prevalent ST type among contemporary CRAb isolates identified in US hospitals, however, new STs are emerging, most notably ST499. Significant diversity was seen among chromosomal blaOXA-51-group carbapenemase, intrinsic blaADC-group cephalosporinase and plasmid-mediated blaOXA-group carbapenemase genes, which likely represented diversification within the STs. Correlations between clinical presentation and outcomes and the genomic features of the infecting isolates are being investigated