Faculty Bibliography

We present real-world data on patients switching from anti-CD20s to fumarates for various motivations in this retrospective observational study of 43 patients from three multiple sclerosis centers. Recurrent infections on anti-CD20s were the most common reason for switching to fumarates. Patients experienced limited disease activity on fumarates (83.7% were free from relapse and new MRI lesions), suggesting effectiveness was maintained. Of the 16.3% with disease activity on fumarates, 57.1% also had disease activity on anti-CD20s. Tolerability was the main reason for discontinuing fumarates. Future studies will provide additional insight into how to effectively and safely transition from anti-CD20s to fumarates.

BACKGROUND/UNASSIGNED:Pyridostigmine bromide is a short-acting carbamate acetylcholinesterase inhibitor that has been shown to acutely augment parasympathetic signaling in cardiovascular disease populations. OBJECTIVE/UNASSIGNED:This study was undertaken to characterize pharmacodynamics, safety, and tolerability of pyridostigmine during repeated dosing in patients with heart failure. METHODS/UNASSIGNED:A prospective ascending-dose, forced titration, double-blind Phase II randomized clinical trial was conducted to compare the effects of pyridostigmine bromide (15, 30, and 60 mg TID over 8 weeks) versus matching placebo on red blood cell (RBC) acetylcholinesterase activity, cholinergic side effects, and physiologic measures of parasympathetic heart rate modulation and sympathovagal balance in ambulatory patients with chronic systolic heart failure. RESULTS/UNASSIGNED:< 0.001 vs placebo). Physiologic measures of parasympathetic heart rate modulation and sympathovagal balance did not differ between treatment groups. In the pyridostigmine bromide group, RBC acetylcholinesterase activity was not significantly associated with postexercise parasympathetic heart modulation. CONCLUSIONS/UNASSIGNED:Pyridostigmine bromide administered over 8 weeks was associated with a significant reduction of RBC acetylcholinesterase activity and relatively mild symptoms of cholinergic excess, but changes in parasympathetic signaling in the sinoatrial node previously reported after acute administration were not observed. Further investigations are needed to delineate pharmacodynamic and pathobiological factors contributing to these findings. ClinicalTrials.gov identifier: NCT01415921.

BACKGROUND/UNASSIGNED:Most patients with cervical synovial cysts (CSC) present with radiculopathy and/or myelopathy. MR studies are the gold standard for diagnosing CSC, and typically show hypointense T1/hyperintense T2 lesions, with occasional cyst-wall enhancement and additional cyst-wall calcification. Surgery typically warrants focal cyst resection/ decompression with/without an instrumented fusion. Here, we reviewed the diagnosis/treatment of a 76-year-old male with a CSC, and C5-C6/C6-C7 , and C7-T1 stenosis. We further provided a select review of the literature. METHODS/UNASSIGNED:For 3 months, a 76-year-old-male experienced progressive bilateral/arm pain (i.e., radiculopathy), and one week of increased right upper/right lower extremity weakness with loss of balance (i.e., myelopathy). The MR with/without contrast and non contrast CT studies documented moderate C5-C6/C6-C7 stenosis and a large, likely synovial cyst filling the right-side of the spinal canal at the C7-T1 level (i.e, 12 mm x 9 mmx 19 mm). RESULTS/UNASSIGNED:The patient urgently underwent excision of the large right C7-T1 synovial cyst, along with a C6-T2 laminectomy for stenosis, and a C4-T4 instrumented fusion. At 4-postoperative months, the patient was neurologically intact. The repeated X-rays performed at 2, 6, and 12 weeks postoperatively documented maintained alignment, while the MR scan confirmed adequate cord decompression without myelomalacia. CONCLUSION/UNASSIGNED:A 76-year-old male with increased right-sided myeloradiculopathy, successfully underwent resection of a right-sided C7-T1 synovial cyst filling the spinal canal, a C6-T2 laminectomy for stenosis, and a C4-T4 instrumented fusion. Four months postoperatively, the patient was neurologically intact, with postoperative X-rays showing stable alignment. Further, the follow-up MR documented no residual cord/root compression, or myelomalacia. Here, we have provided a review of this case and select literature regarding the diagnosis and surgery for CSC.

Individuals with Lewy body dementia (LBD) rely on family caregivers. Caregiving demands limit caregivers' ability to attend to their own health needs, increasing their vulnerability to the psychological effects of caregiving. We previously piloted a peer mentoring intervention with experienced (mentor) and less experienced (mentee) LBD caregivers. Matched mentor-mentee dyads spoke weekly for 16 weeks, guided by an intervention handbook. LBD knowledge and attitudes towards dementia improved post-intervention. We hypothesized that caregiver health status moderates response to peer mentoring. Post hoc analyses (N = 30 dyads) showed that 75% of mentees and 66% of mentors endorsed ≥1 comorbidity. Mentees and mentors with comorbidities showed greater improvement in LBD knowledge postintervention (P = 0.039) and dementia attitudes post-training (P = 0.016), respectively. Caregivers with comorbidities and thus greater exposure to health care may derive excess benefit from an effective LBD caregiver intervention than healthier counterparts, enhancing both the objective knowledge and their confidence in caring for their loved ones.

SARS-CoV-2 infection has been associated with increased autoimmune disease risk. Past studies have not aligned regarding the most prevalent autoimmune diseases after infection, however. Furthermore, the relationship between infection severity and new autoimmune disease risk has not been well examined. We used RECOVER's electronic health record (EHR) networks, N3C, PCORnet, and PEDSnet, to estimate types and frequency of autoimmune diseases arising after SARS-CoV-2 infection and assessed how infection severity related to autoimmune disease risk. We identified patients of any age with SARS-CoV-2 infection between April 1, 2020 and April 1, 2021, and assigned them to a World Health Organization COVID-19 severity category for adults or the PEDSnet acute COVID-19 illness severity classification system for children (<age 21). We collected baseline covariates from the EHR in the year pre-index infection date and followed patients for 2 years for new autoimmune disease, defined as ≥ 2 new ICD-9, ICD-10, or SNOMED codes in the same concept set, starting >30 days after SARS-CoV-2 infection index date and occurring ≥1 day apart. We calculated overall and infection severity-stratified incidence ratesper 1000 person-years for all autoimmune diseases. With least severe COVID-19 severity as reference, survival analyses examined incident autoimmune disease risk. The most common new-onset autoimmune diseases in all networks were thyroid disease, psoriasis/psoriatic arthritis, and inflammatory bowel disease. Among adults, inflammatory arthritis was the most common, and Sjögren's disease also had high incidence. Incident type 1 diabetes and hematological autoimmune diseases were specifically found in children. Across networks, after adjustment, patients with highest COVID-19 severity had highest risk for new autoimmune disease vs. those with least severe disease (N3C: adjusted Hazard Ratio, (aHR) 1.47 (95%CI 1.33-1.66); PCORnet aHR 1.14 (95%CI 1.02-1.26); PEDSnet: aHR 3.14 (95%CI 2.42-4.07)]. Overall, severe acute COVID-19 was most strongly associated with autoimmune disease risk in three EHR networks.

BACKGROUND:Binimetinib and selumetinib are two mitogen-activated protein kinase kinase (MEK) inhibitors used to treat low-grade gliomas and plexiform neurofibromas. Cutaneous toxicities are commonly associated with MEK inhibitors; however, limited studies have examined cutaneous effects in a pediatric population or whether toxicities vary between MEK inhibitors. METHODS:We conducted an IRB-approved, single-center, retrospective review of pediatric neuro-oncology patients on binimetinib or selumetinib who presented to NYU from April 2016 through July 2022. RESULTS:Forty-six children met inclusion criteria (23 females, 23 males) with a mean age of 11.7 years. Thirty-three were treated with binimetinib and 13 with selumetinib. Dermatologic adverse events were encountered in 97.8% of the cohort, and the most common were acneiform eruption (63.0%), paronychia (58.7%), and xerosis (54.3%). Children 12 years and older were more likely to have acneiform eruption (p < 0.001) and seborrheic dermatitis (p < 0.001), while children under 12 were more likely to have xerosis (p = 0.037). The incidence of cutaneous adverse events was significantly different between MEK inhibitors for folliculitis and hair pigment dilution (39.4% binimetinib, 0% selumetinib, p = 0.009). Significantly, more patients required MEK inhibitor dose reduction/hold on binimetinib (87.9%) than selumetinib (46.2%) (p = 0.006). Severity of cutaneous disease was not associated with tumor response. CONCLUSIONS:Our study confirms dermatologic adverse events are common in children on MEK inhibitors. Age appears to be associated with increased likelihood of certain cutaneous reactions. Overall, the selumetinib patients in our cohort presented with less severe adverse events and decreased risk of MEK inhibitor dose reduction/hold. Our results will aid clinicians in providing appropriate counseling, treatments, and improved preventive care.

INTRODUCTION/UNASSIGNED:White matter hyperintensity (WMH) is a hallmark imaging biomarker of cerebral small vessel disease and are strongly associated with vascular cognitive impairment in the elderly. Morphological changes in large extracranial brain-feeding arteries, such as the internal carotid (ICA) and vertebral arteries (VA), may alter intracranial hemodynamics and contribute to WMH development. This study examined the relationship between arterial tortuosity and WMHs using magnetic resonance angiography (MRA). METHODS/UNASSIGNED:Seventy-eight participants underwent time-of-flight (TOF) MRA and phase-contrast (PC) MRI to assess arterial morphology and blood flow. After excluding three for poor image quality, 75 subjects were analyzed. Arterial tortuosity was quantified using the inflection count metric (ICM) and ICA angle. Global cerebral blood flow (CBF) was estimated with PC-MRI and compared against pseudo-continuous arterial spin labeling (pCASL) to determine whether it could be a reliable surrogate measurement to reflect intracranial blood supply. RESULTS/UNASSIGNED:Participants with severe WMHs (Fazekas ≥2) demonstrated greater tortuosity (higher ICM and larger ICA angles) and lower blood flow than those with mild WMHs. Females showed more tortuous arteries, greater WMH burden, and higher susceptibility to hypoperfusion. Correlation analyses revealed a positive association between tortuosity and WMH volume. DISCUSSION/UNASSIGNED:These findings highlight the role of extracranial arterial tortuosity in WMH burden and reveal sex-specific differences in vascular vulnerability. The results underscore the need for further investigation into how age-related vascular remodeling contributes to WMH development and cognitive decline.

Repetitive head impacts are common in contact and collision sports and are linked to structural brain changes and an elevated risk of neurodegenerative diseases such as Chronic Traumatic Encephalopathy. Identifying early in vivo structural markers remains challenging. Although diagnosis currently requires post-mortem confirmation, clinical symptoms, including cognitive impairment and behavioural changes, are reflected in the diagnosis of Traumatic Encephalopathy Syndrome. These symptoms align with dysfunction in key brain regions-amygdala, hippocampus and thalamus-which support memory, emotion and behaviour and commonly show tau pathology in Chronic Traumatic Encephalopathy. This study uses shape analysis to examine structural differences in these regions between former American football players and unexposed asymptomatic controls and evaluates the influence of age, head impact exposure and clinical diagnosis on brain structure. We analyzed brain morphology in former American football players (n = 163) and unexposed, asymptomatic controls (n = 53). Structural segmentation was performed with FreeSurfer 7.1, and the shape analysis pipeline was used to generate subregional reconstructions. Vertex-level morphometry, based on the logarithm of the Jacobian determinant and radial distance, quantified local surface area dilation and thickness. Group differences were examined with covariate-adjusted linear regression models contrasting football players and controls, as well as participants with and without a Traumatic Encephalopathy Syndrome diagnosis. Partial correlations examined the influence of age, age of first football exposure and cumulative head impact index metrics, including frequency, linear acceleration and rotational force. Models were adjusted accordingly for age, body mass index, education, race, imaging site, apolipoprotein

BACKGROUND/UNASSIGNED:Focal task-specific dystonia of the musicians' arm (FTSDma) is an unusual and challenging disorder, often causing significant disability with loss of performing careers. The etiology and optimal management of this disorder remains unclear. METHODS/UNASSIGNED:We reviewed records and videos of 173 patients with FTSDma, 50 patients with writer's cramp (WC), and 16 with other forms of arm dystonia (OD), evaluated by a single examiner in clinical practice over a 25-year period. Detailed analysis of clinical features and videotaped examinations in slow motion (what we call "deep phenotyping") allowed separation of patients into four categories: "precision-grip" dystonia (groups I and III); "power-grip" dystonia (group II); and "proximal dystonia" (group IV). We compared these results to deep phenotyping of patients with FTSDma, WC and OD patients reported in the literature. RESULTS/UNASSIGNED:FTSDma usually affects men, involves the right hand, and begins in the fourth decade. The precision hand of pianists and guitarists (digits 1, 2, 3) was preferentially affected in the right arm, and many of the remaining patients involved the power hand of either arm (digits 3, 4, 5). The dystonic phenotype of the bow arm of string players and drumming arm of stick drummers bore striking resemblance to WC and racquet dystonia, almost always involving the wrist, forearm or shoulder. CONCLUSIONS/UNASSIGNED:Deep phenotyping of FTSDma reveals similarities in dystonic phenotype between instrument classes, likely related to shared technical demands, and unexpected similarities between other forms of task-specific upper extremity dystonia. A network model to explain these findings is proposed.

Leptomeningeal carcinomatosis (LC) is a severe complication of metastatic breast cancer (mBC), with rising incidence. The prognosis for patients with LC has been poor, with a median overall survival of approximately four months. However, recent therapeutic advances, in particular the introduction of trastuzumab deruxtecan have dramatically changed the landscape of CNS metastases and improved outcomes. Here, we present the case of a 42-year-old woman with recurrent HER2+ breast cancer who developed extensive LC after multiple lines of treatment. Despite progressive disease, the patient exhibited a sustained response to trastuzumab deruxtecan, a novel antibody-drug conjugate (ADC), for 15 months, which was further extended by adding tucatinib. This case underscores the potential of ADCs, like trastuzumab deruxtecan, in controlling both brain metastases and leptomeningeal disease, offering hope for prolonged survival in patients with aggressive HER2+ mBC. Additionally, we highlight the evolving role of clinical trials, molecular profiling, and interdisciplinary care in managing this challenging condition. Ongoing trials continue to investigate new therapeutic options for HER2+ mBC with CNS involvement, promising to further improve outcomes and quality of life for patients facing this devastating disease.