Faculty Bibliography

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a recently described CNS inflammatory disorder that may manifest with optic neuritis, myelitis, seizures, and/or acute disseminated encephalomyelitis. While MOG-specific antibodies in patients with MOGAD are IgG1, a T-cell-dependent antibody isotype, immunologic mechanisms of this disease are not fully understood. Thymic hyperplasia can be associated with certain autoimmune diseases. In this report we describe a case of MOGAD associated with thymic hyperplasia in a young adult.

We describe a woman with a history of relapsing acute optic neuritis and perineuritis. Testing failed to confirm a specific diagnosis; hence, she was diagnosed with seronegative neuromyelitis optica spectrum disorder and treated with the immunotherapy rituximab, later in conjunction with mycophenolate mofetil. She achieved a durable remission for 9 years until she presented with paresthesia affecting her left fifth digit, right proximal thigh, and left foot, while also reporting a 25-pound weight loss over the prior 3 months. New imaging demonstrated a longitudinally extensive and enhancing optic nerve, in conjunction with multifocal enhancing lesions within the spinal cord, in a skip-like distribution. The differential diagnosis is discussed.

A woman presented at age 18 years with partial myelitis and diplopia and experienced multiple subsequent relapses. Her MRI demonstrated T2 abnormalities characteristic of multiple sclerosis (MS) (white matter ovoid lesions and Dawson fingers), and CSF demonstrated an elevated IgG index and oligoclonal bands restricted to the CSF. Diagnosed with clinically definite relapsing-remitting MS, she was treated with various MS disease-modifying therapies and eventually began experiencing secondary progression. At age 57 years, she developed an acute longitudinally extensive transverse myelitis and was found to have AQP4 antibodies by cell-based assay. Our analysis of the clinical course, radiographic findings, molecular diagnostic methods, and treatment response characteristics support the hypothesis that our patient most likely had 2 CNS inflammatory disorders: MS, which manifested as a teenager, and neuromyelitis optica spectrum disorder, which evolved in her sixth decade of life. This case emphasizes a key principle in neurology practice, which is to reconsider whether the original working diagnosis remains tenable, especially when confronted with evidence (clinical and/or paraclinical) that raises the possibility of a distinctively different disorder.

PURPOSE/OBJECTIVE:Flourine-18-flortaucipir tau positron emission tomography (PET) was developed for the detection for Alzheimer's disease. Human imaging studies have begun to investigate its use in chronic traumatic encephalopathy (CTE). Flortaucipir-PET to autopsy correlation studies in CTE are needed for diagnostic validation. We examined the association between end-of-life flortaucipir PET and postmortem neuropathological measurements of CTE-related tau in six former American football players. METHODS:Three former National Football League players and three former college football players who were part of the DIAGNOSE CTE Research Project died and agreed to have their brains donated. The six players had flortaucipir (tau) and florbetapir (amyloid) PET prior to death. All brains from the deceased participants were neuropathologically evaluated for the presence of CTE. On average, the participants were 59.0 (SD = 9.32) years of age at time of PET. PET scans were acquired 20.33 (SD = 13.08) months before their death. Using Spearman correlation analyses, we compared flortaucipir standard uptake value ratios (SUVRs) to digital slide-based AT8 phosphorylated tau (p-tau) density in a priori selected composite cortical, composite limbic, and thalamic regions-of-interest (ROIs). RESULTS:Four brain donors had autopsy-confirmed CTE, all with high stage disease (n = 3 stage III, n = 1 stage IV). Three of these four met criteria for the clinical syndrome of CTE, known as traumatic encephalopathy syndrome (TES). Two did not have CTE at autopsy and one of these met criteria for TES. Concomitant pathology was only present in one of the non-CTE cases (Lewy body) and one of the CTE cases (motor neuron disease). There was a strong association between flortaucipir SUVRs and p-tau density in the composite cortical (ρ = 0.71) and limbic (ρ = 0.77) ROIs. Although there was a strong association in the thalamic ROI (ρ = 0.83), this is a region with known off-target binding. SUVRs were modest and CTE and non-CTE cases had overlapping SUVRs and discordant p-tau density for some regions. CONCLUSIONS:Flortaucipir-PET could be useful for detecting high stage CTE neuropathology, but specificity to CTE p-tau is uncertain. Off-target flortaucipir binding in the hippocampus and thalamus complicates interpretation of these associations. In vivo biomarkers that can detect the specific p-tau of CTE across the disease continuum are needed.

INTRODUCTION/BACKGROUND:The presentation, risk factors, and etiologies of white matter hyperintensities (WMH) in people exposed to repetitive head impacts are unknown. We examined the burden and distribution of WMH, and their association with years of play, age of first exposure, and clinical function in former American football players. METHODS:A total of 149 former football players and 53 asymptomatic unexposed participants (all men, 45-74 years) completed fluid-attenuated inversion recovery magnetic resonance imaging, neuropsychological testing, and self-report neuropsychiatric measures. Lesion Segmentation Toolbox estimated WMH. Analyses were performed in the total sample and stratified by age 60. RESULTS:In older but not younger participants, former football players had greater total, frontal, temporal, and parietal log-WMH compared to asymptomatic unexposed men. In older but not younger former football players, greater log-WMH was associated with younger age of first exposure to football and worse executive function. DISCUSSION/CONCLUSIONS:In older former football players, WMH may have unique presentations, risk factors, and etiologies. HIGHLIGHTS/CONCLUSIONS:Older but not younger former football players had greater total, frontal, temporal, and parietal lobe white matter hyperintensities (WMH) compared to same-age asymptomatic unexposed men. Younger age of first exposure to football was associated with greater WMH in older but not younger former American football players. In former football players, greater WMH was associated with worse executive function and verbal memory.

BACKGROUND:The diagnosis of multiple sclerosis (MS) requires demyelinating events that are disseminated in time and space. Peripapillary retinal nerve fiber layer (pRNFL) thickness as measured by optical coherence tomography (OCT) distinguishes eyes with a prior history of acute optic neuritis (ON) and may provide evidence to support a demyelinating attack. OBJECTIVE:To investigate whether a deep learning (DL)-based network can distinguish between eyes with prior ON and healthy control (HC) eyes using peripapillary ring scans. METHODS:We included 1033 OCT scans from 415 healthy eyes (213 HC subjects) and 510 peripapillary ring scans from 164 eyes with prior acute ON (140 patients with MS). Data were split into 70% training, 15% validation, and 15% test data. We included 102 OCT scans from 80 healthy eyes (40 HC) and 61 scans from 40 ON eyes (31 MS patients) from an independent second center. Receiver operating characteristic curve analyses with area under the curve (AUC) were used to investigate performance. RESULTS:We used a dilated residual convolutional neural network for the classification. The final network had an accuracy of 0.85 and an AUC of 0.86, whereas pRNFL only had an AUC of 0.77 in recognizing ON eyes. Using data from a second center, the network achieved an accuracy of 0.77 and an AUC of 0.90 compared to pRNFL, which had an AUC of 0.84. INTERPRETATION:DL-based disease classification of prior ON is feasible and has the potential to outperform thickness-based classification of eyes with and without history of prior ON.

BACKGROUND:Limited data exists evaluating predictors of long-term outcomes after hospitalization for COVID-19. METHODS:We conducted a prospective, longitudinal cohort study of patients hospitalized for COVID-19. The following outcomes were collected at 6 and 12-months post-diagnosis: disability using the modified Rankin Scale (mRS), activities of daily living assessed with the Barthel Index, cognition assessed with the telephone Montreal Cognitive Assessment (t-MoCA), Neuro-QoL batteries for anxiety, depression, fatigue and sleep, and post-acute symptoms of COVID-19. Predictors of these outcomes, including demographics, pre-COVID-19 comorbidities, index COVID-19 hospitalization metrics, and life stressors, were evaluated using multivariable logistic regression. RESULTS:Of 790 COVID-19 patients who survived hospitalization, 451(57%) completed 6-month (N = 383) and/or 12-month (N = 242) follow-up, and 77/451 (17%) died between discharge and 12-month follow-up. Significant life stressors were reported in 121/239 (51%) at 12-months. In multivariable analyses, life stressors including financial insecurity, food insecurity, death of a close contact and new disability were the strongest independent predictors of worse mRS, Barthel Index, depression, fatigue, and sleep scores, and prolonged symptoms, with adjusted odds ratios ranging from 2.5 to 20.8. Other predictors of poor outcome included older age (associated with worse mRS, Barthel, t-MoCA, depression scores), baseline disability (associated with worse mRS, fatigue, Barthel scores), female sex (associated with worse Barthel, anxiety scores) and index COVID-19 severity (associated with worse Barthel index, prolonged symptoms). CONCLUSIONS:Life stressors contribute substantially to worse functional, cognitive and neuropsychiatric outcomes 12-months after COVID-19 hospitalization. Other predictors of poor outcome include older age, female sex, baseline disability and severity of index COVID-19.

Saccadic slowing as a component of supranuclear saccadic gaze palsy is an important diagnostic sign in multiple neurologic conditions, including degenerative, inflammatory, genetic, or ischemic lesions affecting brainstem structures responsible for saccadic generation. Little attention has been given to the accuracy with which clinicians correctly identify saccadic slowing. We compared clinician (n = 19) judgements of horizontal and vertical saccade speed on video recordings of saccades (from 9 patients with slow saccades, 3 healthy controls) to objective saccade peak velocity measurements from infrared oculographic recordings. Clinician groups included neurology residents, general neurologists, and fellowship-trained neuro-ophthalmologists. Saccades with normal peak velocities on infrared recordings were correctly identified as normal in 57% (91/171; 171 = 9 videos × 19 clinicians) of clinician decisions; saccades determined to be slow on infrared recordings were correctly identified as slow in 84% (224/266; 266 = 14 videos × 19 clinicians) of clinician decisions. Vertical saccades were correctly identified as slow more often than horizontal saccades (94% versus 74% of decisions). No significant differences were identified between clinician training levels. Reliable differentiation between normal and slow saccades is clinically challenging; clinical performance is most accurate for detection of vertical saccade slowing. Quantitative analysis of saccade peak velocities enhances accurate detection and is likely to be especially useful for detection of mild saccadic slowing.

Although visual symptoms are common following concussion, quantitative measures of visual function are missing from concussion evaluation protocols on the athletic sideline. For the past half century, rapid automatized naming (RAN) tasks have demonstrated promise as quantitative neuro-visual assessment tools in the setting of head trauma and other disorders but have been previously limited in accessibility and scalability. The Mobile Interactive Cognitive Kit (MICK) App is a digital RAN test that can be downloaded on most mobile devices and can therefore provide a quantitative measure of visual function anywhere, including the athletic sideline. This investigation examined the feasibility of MICK App administration in a cohort of Division 1 college football players. Participants (n = 82) from a National Collegiate Athletic Association (NCAA) Division 1 football team underwent baseline testing on the MICK app. Total completion times of RAN tests on the MICK app were recorded; magnitudes of best time scores and between-trial learning effects were determined by paired t-test. Consistent with most timed performance measures, there were significant learning effects between the two baseline trials for both RAN tasks on the MICK app: Mobile Universal Lexicon Evaluation System (MULES) (p < 0.001, paired t-test, mean improvement 13.3 s) and the Staggered Uneven Number (SUN) (p < 0.001, mean improvement 3.3 s). This study demonstrated that the MICK App can be feasibly administered in the setting of pre-season baseline testing in a Division I environment. These data provide a foundation for post-injury sideline testing that will include comparison to baseline in the setting of concussion.