Faculty Bibliography

Huntington disease, a neurodegenerative disease characterized by progressive motor, behavioral, and cognitive decline, is caused by a CAG trinucleotide repeat expansion in the huntingtin gene on chromosome 4. Current treatments target symptom management because there are no disease-modifying therapies at this time. Investigation of RNA-based and DNA-based treatment strategies are emerging and hold promise of possible future disease-modifying therapy.

Background and aims: In neurogenic orthostatic hypotension (nOH), standing blood pressure (BP) falls due to inadequate norepinephrine (NE) release. Ampreloxetine, a novel, long-acting, NE reuptake inhibitor, has shown durable symptom improvement in subjects with nOH associated with synucleinopathies. The objective of this study was to evaluate BP regulation in subjects with symptomatic nOH treated with open-label ampreloxetine.
Method(s): In a phase 2 study, subjects received ampreloxetine once-daily (3-20mg) for up to 20 weeks, with 4-week follow-up after ampreloxetine withdrawal. Assessments included Orthostatic Hypotension Symptom Assessment Item 1 score (OHSA#1; dizziness, lightheadedness, feeling faint); standing/sitting/supine systolic BP (SBP); standing duration; and plasma NE.
Result(s): 17 symptomatic subjects (baseline OHSA#1 score >4) were enrolled (mean age, 65 years). Mean increase in 3-minute standing SBP from baseline at Weeks 4 and 20 was 9.0mmHg and 10.8mmHg, respectively; >50% of subjects maintained SBP >80mmHg. Sitting SBP changes were less, with little change in supine SBP. At Week 4, 67% of subjects could stand for >5 mins, 31% improvement from baseline. NE plasma levels rose from pre-dose to Week 4 (1664.93-2231.67pmol/l). Baseline NE plasma levels correlated with standing BP increase. Ampreloxetine was well tolerated. Durable symptom improvement in nOH was accompanied by increase in standing and sitting SBP, standing duration, and NE plasma levels, with little effect on supine SBP.
Conclusion(s): These encouraging findings on BP regulation in nOH with ampreloxetine treatment for up to 5 months are being evaluated in ongoing Phase 3, double-blind, confirmatory studies in subjects with nOH

BACKGROUND:Optical coherence tomography (OCT) studies have demonstrated differences between people with schizophrenia and controls. Many questions remain including the agreement between scanners. The current study seeks to determine inter-device agreement of OCT data in schizophrenia compared to controls and to explore the relations between OCT and visual function measures. METHODS:Participants in this pilot study were 12 individuals with schizophrenia spectrum disorders and 12 age- and sex-matched controls. Spectralis and Cirrus OCT machines were used to obtain retinal nerve fiber layer (RNFL) thickness and macular volume. Cirrus was used to obtain ganglion cell layer + inner plexiform layer (GCL + IPL) thickness. Visual function was assessed with low-contrast visual acuity and the King-Devick test of rapid number naming. RESULTS:There was excellent relative agreement in OCT measurements between the two machines, but poor absolute agreement, for both patients and controls. On both machines, people with schizophrenia showed decreased macular volume but no difference in RNFL thickness compared to controls. No between-group difference in GCL + IPL thickness was found on Cirrus. Controls showed significant associations between King-Devick performance and RNFL thickness and macular volume, and between low-contrast visual acuity and GCL + IPL thickness. Patients did not show significant associations between OCT measurements and visual function. CONCLUSIONS:Good relative agreement suggests that the offset between machines remains constant and should not affect comparisons between groups. Decreased macular volume in individuals with schizophrenia on both machines supports findings of prior studies and provides further evidence that similar results may be found irrespective of OCT device.

BACKGROUND AND PURPOSE/OBJECTIVE:Mechanical circulatory support (MCS) devices are commonly used in heart failure patients. These devices carry risk for presumably embolic and additionally hemorrhagic stroke. Alterations in blood flow play a key role in stroke pathophysiology, and we aimed to learn more about hemodynamic compromise. In this study, we used transcranial Doppler (TCD) ultrasound to define hemodynamics of commonly used nonpulsatile MCS devices, as well as pulsatile devices, with special attention to the total artificial heart (TAH). METHODS:From 2/2013 through 12/2016, we prospectively enrolled patients with MCS who underwent TCD imaging. We analyzed TCD parameters, including peak systolic velocity, end-diastolic velocity, pulsatility indices (PIs), and number of high-intensity transient signals. Waveform morphologies were compared between various MCS devices. RESULTS:We performed 132 TCD studies in 86 MCS patients. Waveforms in patients supported by venoarterial-extracorporeal membrane oxygenation demonstrated continuous flow without clear systolic peaks with an average (±SD) PI of .43 (±.2). PIs were low in patients with continuous-flow left ventricular assist devices with a mean PI of .32 (±.13). Impella patients had morphologically distinct pulsatile waveforms and a higher mean PI of .65 (±.24). In intra-arterial balloon pump patients, mean PI was 1.01 (±.16) and diastolic upstrokes were pronounced. In TAH patients, mean middle cerebral artery velocity of 79.69 (±32.33) cm/seconds and PI of .74 (±.14) approached normal values. CONCLUSION/CONCLUSIONS:TCD can detect characteristic waveforms in patients supported by various MCS devices. These device-specific TCD patterns are recognizable and reproducible.

Blindness and vision impairment are unpredictable complications of tuberculous meningitis (TBM) that are often unrecognized in the acute stages of illness due to inability to assess vision in patients with depressed levels of consciousness or confusion. We present a patient with definite TBM confirmed by positive Xpert MTB/RIF assay of cerebrospinal fluid (CSF) who developed binocular blindness two weeks after diagnosis and initiation of standard anti-tuberculosis treatment (ATT). Ophthalmological exam demonstrated complete bilateral abducens nerve palsies, impaired pupillary responses to light, normal optic discs, and visual acuity of hand motion only in each eye. Brain CT showed progressive enlargement of the third and lateral ventricles. We managed the patient medically with dexamethasone, acetazolamide, and substitution of moxifloxacin for ethambutol. Serial brain CTs confirmed gradual resolution of hydrocephalus. The patient had complete neurological recovery at six months except for residual blindness in the right eye. Visual acuity in the left eye recovered to normal (20/20). The assessment and management of vision impairment in TBM is discussed.

OBJECTIVE:To establish cytometry profiles associated with disease stages and immunotherapy in MS. METHODS:Demographic/clinical data and peripheral blood samples were collected from 227 patients with MS and 82 sex- and age-matched healthy controls (HCs) enrolled in a cross-sectional study at 4 European MS centers (Spain, Italy, Germany, and Norway). Flow cytometry of isolated peripheral blood mononuclear cells was performed in each center using specifically prepared antibody-cocktail Lyotubes; data analysis was centralized at the Genoa center. Differences in immune cell subsets were assessed between groups of untreated patients with relapsing-remitting or progressive MS (RRMS or PMS) and HCs and between groups of patients with RRMS taking 6 commonly used disease-modifying drugs. RESULTS:T-regulatory and B-regulatory cells. CONCLUSIONS:Our highly standardized, multisite cytomics data provide further understanding of treatment impact on MS immunophenotype and could pave the way toward monitoring immune cells to help clinical management of MS individuals.

BACKGROUND AND PURPOSE/OBJECTIVE:The brain stem is a complex configuration of small nuclei and pathways for motor, sensory, and autonomic control that are essential for life, yet internal brain stem anatomy is difficult to characterize in living subjects. We hypothesized that the 3D fast gray matter acquisition T1 inversion recovery sequence, which uses a short inversion time to suppress signal from white matter, could improve contrast resolution of brain stem pathways and nuclei with 3T MR imaging. MATERIALS AND METHODS/METHODS:-space to reduce motion; total scan time = 58 minutes). One subject returned for an additional 5-average study that was combined with a previous session to create a highest quality atlas for anatomic assignments. A 1-mm isotropic resolution, 12-minute version, proved successful in a patient with a prior infarct. RESULTS:The fast gray matter acquisition T1 inversion recovery sequence generated excellent contrast resolution of small brain stem pathways in all 3 planes for all 10 subjects. Several nuclei could be resolved directly by image contrast alone or indirectly located due to bordering visualized structures (eg, locus coeruleus and pedunculopontine nucleus). CONCLUSIONS:The fast gray matter acquisition T1 inversion recovery sequence has the potential to provide imaging correlates to clinical conditions that affect the brain stem, improve neurosurgical navigation, validate diffusion tractography of the brain stem, and generate a 3D atlas for automatic parcellation of specific brain stem structures.

OBJECTIVE:To assess the proportion of individuals who report dizziness and/or vertigo during the prodromal phase or headache phase of migraine. METHODS:The databases of MEDLINE and EMBASE were searched for studies on dizziness and/or vertigo during the prodromal phase or headache phase of migraine. Pooled relative frequencies were estimated using a random-effects meta-analysis. RESULTS: = 87%). Study quality was rated 5/9 or below for seven studies and 6/9 or above for two studies. CONCLUSION/CONCLUSIONS:We found that there is a scarcity of literature on dizziness and vertigo as prodromal- and headache-associated symptoms in individuals with migraine. Methodological variations confound comparisons of epidemiological patterns, although it appears that dizziness and vertigo are more frequent during the headache phase of migraine, compared with the prodromal phase. Future studies should ensure use of standardized definitions and rigorous methodology to enable accurate measurements of dizziness and vertigo in migraine.