Faculty Bibliography

OBJECTIVE:To determine the prevalence and associated mortality of well-defined neurologic diagnoses among COVID-19 patients, we prospectively followed hospitalized SARS-Cov-2 positive patients and recorded new neurologic disorders and hospital outcomes. METHODS:We conducted a prospective, multi-center, observational study of consecutive hospitalized adults in the NYC metropolitan area with laboratory-confirmed SARS-CoV-2 infection. The prevalence of new neurologic disorders (as diagnosed by a neurologist) was recorded and in-hospital mortality and discharge disposition were compared between COVID-19 patients with and without neurologic disorders. RESULTS:Of 4,491 COVID-19 patients hospitalized during the study timeframe, 606 (13.5%) developed a new neurologic disorder in a median of 2 days from COVID-19 symptom onset. The most common diagnoses were: toxic/metabolic encephalopathy (6.8%), seizure (1.6%), stroke (1.9%), and hypoxic/ischemic injury (1.4%). No patient had meningitis/encephalitis, or myelopathy/myelitis referable to SARS-CoV-2 infection and 18/18 CSF specimens were RT-PCR negative for SARS-CoV-2. Patients with neurologic disorders were more often older, male, white, hypertensive, diabetic, intubated, and had higher sequential organ failure assessment (SOFA) scores (all P<0.05). After adjusting for age, sex, SOFA-scores, intubation, past history, medical complications, medications and comfort-care-status, COVID-19 patients with neurologic disorders had increased risk of in-hospital mortality (Hazard Ratio[HR] 1.38, 95% CI 1.17-1.62, P<0.001) and decreased likelihood of discharge home (HR 0.72, 95% CI 0.63-0.85, P<0.001). CONCLUSIONS:Neurologic disorders were detected in 13.5% of COVID-19 patients and were associated with increased risk of in-hospital mortality and decreased likelihood of discharge home. Many observed neurologic disorders may be sequelae of severe systemic illness.

Persistent post-traumatic headache (PPTH) is often the most common injury post mild traumatic brain injury (mTBI), reported by 47%-95% of patients. Progressive muscle relaxation (PMR) has level A evidence in preventing migraine and tension headaches. However, research on this behavioral therapy for PPTH, let alone smartphone-delivered, is limited. We performed a single-arm study of prospective patients calling our Concussion Center between June 2017-July 2018. Inclusion criteria were that subjects had to meet ICHD-3 criteria for PPTH secondary to mTBI, have four or more headache days a month, be age 18-85 and 3-12 months post injury, own a smartphone and not tried headache behavioral therapy within the year. We recorded baseline headache and neuropsychiatric data. Using the RELAXaHEAD smartphone application, which has a headache diary and PMR audio files, participants were instructed to record headache symptoms and practice 20 minutes of PMR daily. There were three monthly follow-up assessments. There were 49 subjects enrolled. Basic demographics were: 33 (67%) female with mean age 40.1±14.6 [20,75]. Of the 49 subjects, 15 (31%) had pre-existing headaches. In 11 (22%) subjects, mTBI was sports-related. Subjects reported 17.7±9.3 [4,31] headache days in the month before enrollment, and 49 (100%) experienced over three concussion symptoms. Participants inputted data in the RELAXaHEAD app on average 18.3±12.0 days [0,31] the first month. Number of participants who did PMR over 4 times/week was 12 (24.5%) the first month, 9 (22.5 %) the second month, and 6 (15%) the third month. After three months, 17 (42.5 %) participants continued doing PMR. Participants cited time constraints, forgetfulness, application glitches and repetitiveness as obstacles to practicing PMR. It is feasible to get PPTH subjects to practice behavioral therapy through low-cost smartphone-based PMR two times weekly. Future work will assess efficacy and examine how to optimize barriers to PMR.

BACKGROUND:Eye-hand coordination (EHC) is a sophisticated act that requires interconnected processes governing synchronization of ocular and manual motor systems. Precise, timely and skillful movements such as reaching for and grasping small objects depend on the acquisition of high-quality visual information about the environment and simultaneous eye and hand control. Multiple areas in the brainstem and cerebellum, as well as some frontal and parietal structures, have critical roles in the control of eye movements and their coordination with the head. Although both cortex and cerebellum contribute critical elements to normal eye-hand function, differences in these contributions suggest that there may be separable deficits following injury. METHOD/METHODS:As a preliminary assessment for this perspective, we compared eye and hand-movement control in a patient with cortical stroke relative to a patient with cerebellar stroke. RESULT/RESULTS:We found the onset of eye and hand movements to be temporally decoupled, with significant decoupling variance in the patient with cerebellar stroke. In contrast, the patient with cortical stroke displayed increased hand spatial errors and less significant temporal decoupling variance. Increased decoupling variance in the patient with cerebellar stroke was primarily due to unstable timing of rapid eye movements, saccades. CONCLUSION/CONCLUSIONS:These findings highlight a perspective in which facets of eye-hand dyscoordination are dependent on lesion location and may or may not cooperate to varying degrees. Broadly speaking, the results corroborate the general notion that the cerebellum is instrumental to the process of temporal prediction for eye and hand movements, while the cortex is instrumental to the process of spatial prediction, both of which are critical aspects of functional movement control.

Background: Zinc impairs replication of RNA viruses such as SARS-CoV-1, and may be effective against SARS-CoV-2. However, to achieve adequate intracellular zinc levels, administration with an ionophore, which increases intracellular zinc levels, may be necessary. We evaluated the impact of zinc with an ionophore (Zn+ionophore) on COVID-19 in-hospital mortality rates. Methods: A multicenter cohort study was conducted of 3,473 adult hospitalized patients with reverse-transcriptase-polymerase-chain-reaction (RT-PCR) positive SARS-CoV-2 infection admitted to four New York City hospitals between March 10 through May 20, 2020. Exclusion criteria were: death or discharge within 24h, comfort-care status, clinical trial enrollment, treatment with an IL-6 inhibitor or remdesivir. Patients who received Zn+ionophore were compared to patients who did not using multivariable time-dependent cox proportional hazards models for time to in-hospital death adjusting for confounders including age, sex, race, BMI, diabetes, week of admission, hospital location, sequential organ failure assessment (SOFA) score, intubation, acute renal failure, neurological events, treatment with corticosteroids, azithromycin or lopinavir/ritonavir and the propensity score of receiving Zn+ionophore. A sensitivity analysis was performed using a propensity score-matched cohort of patients who did or did not receive Zn+ionophore matched by age, sex and ventilator status. Results: Among 3,473 patients (median age 64, 1947 [56%] male, 522 [15%] ventilated, 545[16%] died), 1,006 (29%) received Zn+ionophore. Zn+ionophore was associated with a 24% reduced risk of in-hospital mortality (12% of those who received Zn+ionophore died versus 17% who did not; adjusted Hazard Ratio [aHR] 0.76, 95% CI 0.60-0.96, P=0.023). More patients who received Zn+ionophore were discharged home (72% Zn+ionophore vs 67% no Zn+ionophore, P=0.003) Neither Zn nor the ionophore alone were associated with decreased mortality rates. Propensity score-matched sensitivity analysis (N=1356) validated these results (Zn+ionophore aHR for mortality 0.63, 95%CI 0.44-0.91, P=0.015). There were no significant interactions for Zn+ionophore with other COVID-19 specific medications. Conclusions: Zinc with an ionophore was associated with increased rates of discharge home and a 24% reduced risk of in-hospital mortality among COVID-19 patients, while neither zinc alone nor the ionophore alone reduced mortality. Further randomized trials are warranted.

Vision, which requires extensive neural involvement, is often impaired in Alzheimer's disease (AD). Over the last few decades, accumulating evidence has shown that various visual functions and structures are compromised in Alzheimer's dementia and when measured can detect those with dementia from those with normal aging. These visual changes involve both the afferent and efferent parts of the visual system, which correspond to the sensory and eye movement aspects of vision, respectively. There are fewer, but a growing number of studies, that focus on the detection of predementia stages. Visual biomarkers that detect these stages are paramount in the development of successful disease-modifying therapies by identifying appropriate research participants and in identifying those who would receive future therapies. This review provides a summary and update on common afferent and efferent visual markers of AD with a focus on mild cognitive impairment (MCI) and preclinical disease detection. We further propose future directions in this area. Given the ease of performing visual tests, the accessibility of the eye, and advances in ocular technology, visual measures have the potential to be effective, practical, and non-invasive biomarkers of AD.

Saccadic eye movement abnormalities are among the earliest manifestations of Huntington's disease (HD) but are difficult to quantify at the bedside. Similarly, afferent visual pathway involvement in HD is poorly characterised. The objective was to evaluate afferent and efferent visual function in HD. Participants with manifest HD (n = 19) and healthy controls (n = 20) performed the King-Devick test, a timed test of rapid number naming. Binocular high and low-contrast (2.5% and 1.25%) acuities were measured using low-contrast Sloan letter charts, and pupillometric recordings were made using a handheld NeurOptics PLR-3000 pupillometer. The NEI-VFQ-25 questionnaire with 10-item neuro-ophthalmic supplement were also completed. Unified Huntington's Disease Rating Scale (UHDRS) motor score and other clinical and demographic variables were collected. Comparisons between manifest HD and controls were performed using linear regression adjusted for confounders. Mean King-Devick time scores were 102.9 seconds in patients with manifest HD and 48.2 seconds in controls (p < .01, t-test). In unadjusted analyses, binocular high contrast acuity was seven letters (one Snellen line equivalent) lower in manifest HD than controls (p = .043). This effect was similar for low-contrast acuity, but only low-contrast acuity remained statistically significant after adjusting for covariates. Low-contrast acuity also correlated with UHDRS motor score. There were no differences in pupillary reactivity or self-reported vision-related quality of life. In conclusion, HD is associated with reduced low-contrast acuity and abnormal performance on the King-Devick test of rapid number naming. These tests are easy to administer, providing an objective quantitative measure of visual function which could be incorporated into optimised rating scales.

OBJECTIVE:Investigations have found associations of homonymous thinning of the macular ganglion cell/ inner-plexiform layer (GCIPL) with demyelinating lesions in the post-chiasmal visual pathway among patients with multiple sclerosis (MS). Retinal thinning may also occur through retrograde trans-synaptic degeneration, a process by which lesions in post-geniculate visual pathway structures lead to thinning of the GCIPL across thalamic synapses. The purpose of our study was to determine the frequency of homonymous hemimacular thinning that occurs in association with post-chiasmal visual pathway demyelinating lesions in patients with MS and other demyelinating diseases. METHODS:Adult patients with demyelinating diseases (MS, neuromyelitis optica spectrum disorder [NMOSD], myelin oligodendrocyte glycoprotein antibody disease (anti-MOG)) who were participants in an ongoing observational study of visual pathway structure and function were analyzed for the presence of hemimacular GCIPL thinning on OCT scans. Brain MRI scans were examined for the presence of post-geniculate visual pathway demyelinating lesions. RESULTS:Among 135 participants in the visual pathway study, 5 patients (3.7%) had homonymous hemimacular GCIPL thinning. Eleven patients (8.1%) had a whole+half pattern of GCIPL thinning, characterized by hemimacular thinning in one eye and circumferential macular thinning in the contralateral eye. All but one patient with homonymous hemimacular thinning had demyelinating lesions in the post-geniculate visual pathway; however, these lesions were located in both cerebral hemispheres. CONCLUSION/CONCLUSIONS:Homonymous hemimacular thinning in the GCIPL by OCT is associated with post-chiasmal visual pathway demyelinating lesions but it appears to be a relatively uncommon contributor to GCIPL loss. Patients with this pattern of GCIPL often fail to complain of hemifield visual loss. Future studies with prospective and detailed MR imaging may be able to more closely associate demyelinating lesions in anatomically appropriate regions of the post-chiasmal visual pathways with homonymous hemimacular thinning.

OBJECTIVES/OBJECTIVE:Hyponatremia occurs in up to 30% of patients with pneumonia and is associated with increased morbidity and mortality. The prevalence of hyponatremia associated with coronavirus disease 2019 and the impact on outcome is unknown. We aimed to identify the prevalence, predictors, and impact on outcome of mild, moderate, and severe admission hyponatremia compared with normonatremia among coronavirus disease 2019 patients. DESIGN/METHODS:Retrospective, multicenter, observational cohort study. SETTING/METHODS:Four New York City hospitals that are part of the same health network. PATIENTS/METHODS:Hospitalized, laboratory-confirmed adult coronavirus disease 2019 patients admitted between March 1, 2020, and May 13, 2020. INTERVENTIONS/METHODS:None. MEASUREMENTS AND MAIN RESULTS/RESULTS:Hyponatremia was categorized as mild (sodium: 130-134 mmol/L), moderate (sodium: 121-129 mmol/L), or severe (sodium: ≤ 120 mmol/L) versus normonatremia (135-145 mmol/L). The primary outcome was the association of increasing severity of hyponatremia and in-hospital mortality assessed using multivariable logistic regression analysis. Secondary outcomes included encephalopathy, acute renal failure, mechanical ventilation, and discharge home compared across sodium levels using Kruskal-Wallis and chi-square tests. In exploratory analysis, the association of sodium levels and interleukin-6 levels (which has been linked to nonosmotic release of vasopressin) was assessed. Among 4,645 patient encounters, hyponatremia (sodium < 135 mmol/L) occurred in 1,373 (30%) and 374 of 1,373 (27%) required invasive mechanical ventilation. Mild, moderate, and severe hyponatremia occurred in 1,032 (22%), 305 (7%), and 36 (1%) patients, respectively. Each level of worsening hyponatremia conferred 43% increased odds of in-hospital death after adjusting for age, gender, race, body mass index, past medical history, admission laboratory abnormalities, admission Sequential Organ Failure Assessment score, renal failure, encephalopathy, and mechanical ventilation (adjusted odds ratio, 1.43; 95% CI, 1.08-1.88; p = 0.012). Increasing severity of hyponatremia was associated with encephalopathy, mechanical ventilation, and decreased probability of discharge home (all p < 0.001). Higher interleukin-6 levels correlated with lower sodium levels (p = 0.017). CONCLUSIONS:Hyponatremia occurred in nearly a third of coronavirus disease 2019 patients, was an independent predictor of in-hospital mortality, and was associated with increased risk of encephalopathy and mechanical ventilation.