Faculty Bibliography

We present a radiology-pathology case series of 3 patients with coronavirus disease 2019 (COVID-19) with acute ischemic stroke due to fulminant carotid thrombosis overlying mild atherosclerotic plaque and propose a novel stroke mechanism: COVID-associated carotid atherothrombosis.

BACKGROUND:Leucine-rich repeat kinase 2 kinase inhibitors are being vigorously pursued as potential therapeutic options; however, there is a critical need for sensitive and quantitative assays of leucine-rich repeat kinase 2 function and target engagement. OBJECTIVES/OBJECTIVE:Our objective was to compare collection and storage protocols for peripheral blood mononuclear cells, and to determine the optimal conditions for downstream analyses of leucine-rich repeat kinase 2 in PD cohorts. METHODS:Here, we describe enzyme-linked immunosorbent assay-based assays capable of detecting multiple aspects of leucine-rich repeat kinase 2 function at endogenous levels in human tissues. RESULTS:In peripheral blood mononuclear cells from both healthy and affected carriers of the G2019S mutation in leucine-rich repeat kinase 2, we report, for the first time, significantly elevated in vitro kinase activity, while detecting a significant increase in pS935/leucine-rich repeat kinase 2 in idiopathic PD patients. CONCLUSIONS:Quantitative assays such as these described here could potentially uncover specific markers of leucine-rich repeat kinase 2 function that are predictive of disease progression, aid in patient stratification, and be a critical component of upcoming clinical trials. © 2020 International Parkinson and Movement Disorder Society.

OBJECTIVE:To evaluate whether multiple sessions of transcranial direct current stimulation (tDCS) applied to the primary motor (M1) cortex paired with aerobic exercise can improve walking functions in multiple sclerosis (MS). METHODS:MS participants were recruited for a double-blind, parallel-arm, randomized, sham-controlled trial and assigned to 10 sessions (5 d/wk for 2 weeks) of either active or sham tDCS paired with unloaded cycling for 20 minutes. Stimulation was administered over the left M1 cortex (2.5 mA; anode over C3/cathode over FP2). Gait spatiotemporal parameters were assessed using a wearable inertial sensor (10-meter and 2-minute walking tests). Measurements were collected at baseline, end of tDCS intervention, and 4-week postintervention to test for duration of any benefits. RESULTS:A total of 15 participants completed the study, nine in the active and six in the sham condition. The active and sham groups were matched according to gender (50% vs. 40% female), neurologic disability (median EDSS 5.5 vs. 5), and age (mean 52.1 ± 12.9 vs. 53.7 ± 9.8 years). The active group had a significantly greater increase in gait speed (0.87 vs. 1.20 m/s, p < 0.001) and distance covered during the 2-minute walking test (118.53 vs. 133.06 m, p < 0.001) at intervention end compared to baseline. At 4-week follow-up, these improvements were maintained (baseline vs. follow-up: gait speed 0.87 vs. 1.18 m/s, p < 0.001; distance traveled 118.53 vs. 143.82 m, p < 0.001). INTERPRETATION/CONCLUSIONS:Multiple sessions of tDCS paired with aerobic exercise lead to cumulative and persisting improvements in walking and endurance in patients with MS.

OBJECTIVES/OBJECTIVE:To analyze and compare differences between epidemiological and clinical aspects, as well as radiologic findings and treatment, in a series of adult patients with traumatic intracranial hypotension (TIH) and spontaneous intracranial hypotension (SIH) treated at our institution in order to identify predictors of recurrence. BACKGROUND:Cerebrospinal fluid hypotension headache (CSF-HH) is often caused by orthostasis and relieved by recumbency. Etiology can be either traumatic or spontaneous. Indirect signs of CSF hypotension are often observed on brain MRI. The most common therapeutic approach is conservative management and, when necessary, the use of an epidural blood patch. METHODS:Medical history and brain MRI of adult patients consulting our institution with a diagnosis of CSF-HH between January 2010 and March 2019, were retrospectively reviewed. Clinical criteria as per the International Classification of Headache Disorders, 3rd edition, were applied. Presence of typical MRI findings were assessed by two experienced neuroradiologists, previously informed of patients' clinical characteristics. Patients were divided into two different groups, namely: Group A: Spontaneous Intracranial Hypotension (SIH) and Group B: Traumatic Intracranial Hypotension (TIH). Recurrence was defined as return of symptoms after one month of remission. In order to find predictors of recurrent intracranial hypotension the patients were divided into three groups: Recurrent Orthostatic headache (ROH); (33 cases; 25%); Non-Recurrent Orthostatic headache (NROH) (84; 61%) and Patients missing follow-up (20; 15%). The latter were excluded from the regression analysis. RESULTS:137 patients with CSF-HH were identified: 80 traumatic (54 women, age 33.8 ± 10.4 years) and 57 spontaneous (31 women, age 43.9 ± 15.2 years). Median follow-up was 35 months (range: 8 months-9 years). Compared with TIH, patients with SIH showed lower frequency of orthostatic headache and higher frequency of aural fullness. Also, in patients with SIH, brain MRI showed a higher frequency of pachymeningeal enhancement, ventricular collapse, cisternal obliteration, posterior fossa crowding, brainstem distortion, and a more likely presence of subdural collections. Patients with SIH required an epidural blood patch treatment more often, showed higher recurrence rates, and were more prone to develop subdural hematomas. RECURRENCE/UNASSIGNED:As more days elapsed between headache onset and clinical consultation, the presence of spontaneous intracranial hypotension, tinnitus, and thoraco-lumbo-sacral pain were all more common in patients with recurrence. Findings on brain MRI suggesting higher recurrence rates in patients included: ventricular collapse, brainstem distortion, and posterior fossa crowding. Patients treated with invasive therapy (epidural blood patch) presented a higher recurrence rate. In the multivariate regression analysis, the only independent predictor of recurrence after adjusting for age, sex and traumatic vs spontaneous cause of IH, was brainstem distortion diagnosed on MRI (OR 5.13, 95% CI: 1.2-21.7; p = 0.026). CONCLUSIONS:SIH and TIH can no longer be likened, since there is considerable variability in clinical presentation, imaging findings, response to treatment and recurrence rates. Anatomical abnormalities underlying SIH leaks are often complex and not simply a disruption of normal structures as encountered in TIH, which could explain why treatment success is poor and recurrence rates remain high.

Internal and external segments of globus pallidus (GP) exert different functions in basal ganglia circuitry, despite their main connectional systems share the same topographical organization, delineating limbic, associative, and sensorimotor territories. The identification of internal GP sensorimotor territory has therapeutic implications in functional neurosurgery settings. This study is aimed at assessing the spatial coherence of striatopallidal, subthalamopallidal, and pallidothalamic pathways by using tractography-derived connectivity-based parcellation (CBP) on high quality diffusion MRI data of 100 unrelated healthy subjects from the Human Connectome Project. A two-stage hypothesis-driven CBP approach has been carried out on the internal and external GP. Dice coefficient between functionally homologous pairs of pallidal maps has been computed. In addition, reproducibility of parcellation according to different pathways of interest has been investigated, as well as spatial relations between connectivity maps and existing optimal stimulation points for dystonic patients. The spatial organization of connectivity clusters revealed anterior limbic, intermediate associative and posterior sensorimotor maps within both internal and external GP. Dice coefficients showed high degree of coherence between functionally similar maps derived from the different bundles of interest. Sensorimotor maps derived from the subthalamopallidal pathway resulted to be the nearest to known optimal pallidal stimulation sites for dystonic patients. Our findings suggest that functionally homologous afferent and efferent connections may share similar spatial territory within the GP and that subcortical pallidal connectional systems may have distinct implications in the treatment of movement disorders.

OBJECTIVE:To examine autonomic regulation of core body temperature, heart rate (HR), and breathing rate (BR) in response to moderately elevated ambient temperature or moderate physical exercise in a mouse model of Dravet syndrome (DS). METHODS:We studied video-EEG, ECG, respiration, and temperature in mice with global heterozygous Scn1a knockout (KO) (DS mice), interneuron specific Scn1a KO, and wildtype (WT) mice during exposure to increased environmental temperature and moderate treadmill exercise. RESULTS:Core body temperatures of WT and DS mice were similar during baseline. After 15 mins of heat exposure, the peak value was lower in DS than WT mice. In the following mins of heat exposure, the temperature slowly returned close to baseline level in WT, whereas it remained elevated in DS mice. KO of Scn1a in GABAergic neurons caused similar thermoregulatory deficits in mice. During exercise, the HR increase was less prominent in DS than WT mice. After exercise, the HR was significantly more suppressed in DS. The heart rate variability (HRV) was lower in DS than WT mice during baseline and higher in DS during exercise-recovery periods. SIGNIFICANCE/CONCLUSIONS:We found novel abnormalities that expand the spectrum of interictal, ictal, and postictal autonomic dysregulation in DS mice. During mild heat stress, there was a significantly blunted correction of body temperature, and a less suppression of both HR and respiration rate in DS than WT mice. These effects were seen in mice with selective KO of Scn1A in GABAergic neurons. During exercise stress, there was diminished increase in HR, followed by an exaggerated HR suppression and HRV elevation during recovery in DS mice compared to controls. These findings suggest that different environmental stressors can uncover distinct autonomic disturbances in DS mice. Interneurons play an important role in thermoregulation. Understanding the spectrum and mechanisms of autonomic disorders in DS may help develop more effective strategies to prevent seizures and SUDEP.

Nocturnal events of wide variety and concern are frequently reported by patients and their caregivers. To evaluate suspected abnormal events, primary care physicians must first be familiar with normal behaviors, movements and breathing patterns. Abnormal nocturnal events can then be categorized as nocturnal seizure, parasomnia, sleep-related movement disorder or sleep-related breathing disorder. Diagnoses in the above categories can be made clinically; however, it is important to know when to refer for additional evaluation. Comprehensive literature review was undertaken of nocturnal and sleep-related disorders. This guide reviews nocturnal seizures, normal and abnormal nonepileptic movements and behaviors, discusses broad indications for referral for electroencephalography (EEG) or polysomnography (PSG), and guides counseling and management for patients and their families, ultimately aiding in interpretation of both findings and prognosis. Epilepsy syndromes can result in seizures during sleep or adjacent periods of wakefulness. Parasomnias and sleep-related movement disorders tend to also occur in childhood and may be distinguished clinically. Referral to additional specialists for specific studies including EEG or PSG can be necessary, while other times a knowledgeable and vigilant clinician can contribute to a prompt diagnosis based on clinical features. Nocturnal events often can be managed with parental reassurance and watchful waiting, but treatment or evaluation may be needed. Sleep-related breathing disorders are important to recognize as they present very differently in children than in adults and early intervention can be life-saving. This review should allow both primary and subspecialty non-neurologic pediatric and adolescent health care providers to better utilize EEG and PSG as part of a larger comprehensive clinical approach, distinguishing and managing both epileptic and nonepileptic nocturnal disorders of concern while fostering communication across providers to facilitate and coordinate better holistic long-term care of pediatric and adolescent patients.