Faculty Bibliography

OBJECTIVE:To outline strategies for the treatment of migraine which do not require in-person visits to clinic or the emergency department, and to describe ways that health insurance companies can remove barriers to quality care for migraine. BACKGROUND:COVID-19 is a global pandemic causing widespread infections and death. To control the spread of infection we are called to observe "social distancing" and we have been asked to postpone any procedures which are not essential. Since procedural therapies are a mainstay of headache care, the inability to do procedures could negatively affect our patients with migraine. In this manuscript we review alternative therapies, with particular attention to those which may be contra-indicated in the setting of COVID-19 infection. DESIGN/RESULTS/UNASSIGNED:The manuscript reviews the use of telemedicine visits and acute, bridge, and preventive therapies for migraine. We focus on evidence-based treatment where possible, but also describe "real world" strategies which may be tried. In each section we call out areas where changes to rules from commercial health insurance companies would facilitate better migraine care. CONCLUSIONS:Our common goal as health care providers is to maximize the health and safety of our patients. Successful management of migraine with avoidance of in-person clinic and emergency department visits further benefits the current urgent societal goal of maintaining social distance to contain the COVID-19 pandemic.

Background and aims: Distinguishing neurogenic orthostatic hypotension (nOH) from other causes of blood pressure (BP) instability is of pivotal importance in clinical practice. Norcliffe-Kaufmann et al. recently showed that when the ratio between the heart rate increase and the systolic BP fall after 3 minutes of passive head-up tilt (HUT) is <0.492, this indicates nOH. Here we aimed at validating this nOH ratio with standard arm-cuff BP measurements upon active standing (AS).
Method(s): We screened all patients who had undergone cardiovascular autonomic function testing at the Innsbruck Medical University between January 2008 and September 2019.
Result(s): We included 51 patients (27 with Parkinson's disease, 22 with multiple system atrophy) diagnosed with orthostatic hypotension either upon AS or HUT. 49 patients showed no BP overshoot after the Valsalva maneuver and were thus classified as having nOH. Out of these, 27 patients showed a systolic BP fall >=20mmHg in both the HUT and the AS and were considered for further analysis. The nOH ratio was <0.492 for 20 patients during HUT and for 19 patients during the AS. The sensitivity of the nOH ratio for neurogenic OH was therefore 74% upon HUT and 70% upon AS. The correlation between the nOH-ratio upon HUT and AS was strong (rho=0.86, p<0.001).
Conclusion(s): A nOH ratio <0.492 evaluated with standard arm-cuff heart rate and BP measurements has a good sensitivity for nOH both upon HUT and AS. This ratio can be therefore used as bedside nOH screening measure, if no tilt-test facilities are available

Objectives: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder that is characterized by selective degeneration of both upper and lower motor neurons, resulting in paralysis of skeletal muscle and respiratory failure, with death occurring within 2-5 years of diagnosis. 90% of cases are sporadic, and of the 10% that are familial more than 20 genes (>150 mutations) have been found to be associated with ALS, most notably copper/zinc superoxide dismutase (SOD1). SOD1 mutant proteins are believed to cause toxicities in degenerating neurons. Studies suggest that the neuronal and non-neuronal cell contributions to the onset and progression of ALS are complex. It was proposed that there are two phases of neuroinflammation in the spinal cord - the first being an early neuroprotective phase followed by a second late neurotoxic phase. One of the challenges in the study of neuroinflammation is that it is difficult to serially track the disease process, as there are no bona fide biomarkers for onset and progression in ALS. For this reason, we use PET with [¹¹C]PBR28 to track microglial neuroinflammation in the brain and spinal cord. We and others have shown that the receptor for advanced glycation end products (RAGE) is highly expressed in human ALS spinal cord, particularly in microglia, and to an increased degree compared to that of age-matched control subjects. Our previous studies with myeloid/microglia deletion of Ager and treatment with sRAGE (soluble RAGE) suggested that RAGE impairs survival and motor function in Sod1G93Amice. The ultimate goal is to test the hypothesis that RAGE inhibition in either initiation or progression phases of the ALS will prolong survival and maintain motor function in adult Sod1G93Amice.
Method(s): MicroPET/CT (Inveon, Siemens) with [¹¹C]PBR28 was used to track and compare microglial neuroinflammation in the brain and spinal cord of WT vs. ALS mice (110-120 day old), also after treatment with RAGE inhibitors (subject identity was blind to study investigator and data analyst). Using IRW (Inveon Research Workplace, Siemens), several ROIs in the thoracic and lumbar spinal cord (T13, L1, L2, L3) were drawn on the fused PET/CT images to obtain the regional SUVs. An automated atlasbased methodology using Firevoxel (https://urldefense.proofpoint.com/v2/url?u=https-3A__wp.nyu.edu_Firevoxel&d=DwIBAg&c=j5oPpO0eBH1iio48DtsedeElZfc04rx3ExJHeIIZuCs&r=CY_mkeBghQnUPnp2mckgsNSbUXISJaiBQUhM-Uz9W58&m=_uGsTvUTTD_GxqvwK245ZUiiSbzVraIboytFijFDOwU&s=RlC-AQtmqr84rzBwvDmgK_FCVdvbCfsFvuN-dVODTpM&e= ) that we previously developed was used for brain mapping and segmentation to derive regional timeactivity curves (TAC) and SUVs for 20 brain regions.
Result(s): Dynamic regional SUV [¹¹C]PBR28 binding data were obtained and averaged SUVs derived from the last 5 frames (with steady and less variable intensity levels) were compared. Results derived from both spinal cord and brain regions displayed a similar trend with two obvious clusters. Reduced binding was observed for ALS group as compared to WT. RAGE inhibitor-treated ALS mi ce showed increased binding (brain SUV avg. 0.402+/-0.0382 over 20 ROIs) as compared to vehicle-treated (0.157+/-0.0339), suggesting that RAGE inhibition may contribute to the restoration of homeostasis in ALS animals (i.e., their bindings after treatment were closer to those in WT (0.485+/-0.171)). Notably, hypothalamus, brain stem, and olfactory bulb consistently exhibited higher binding, suggesting their role in this regulation.
Conclusion(s): Inconsistent outcomes have been reported in the literature when comparing TSPO ligand binding for imaging neuroinflammation. Our data are consistent with findings from several recent studies; i.e., reduced PBR28 binding was associated with disease state (e.g., in patients with PTSD or alcoholism). A notion that the reduced binding might reflect competition from endogenous TSPO ligands such as cholesterol can't be excluded. The strategies described here will test the hypothesis that pharmacological antagonism of RAGE signal transduction in either initiation or progression phases of the ALS will prolong survival and maintain motor function in adult Sod1G93Amice

OBJECTIVE: Rotator cuff tendon tears are the most common soft tissue injuries in the shoulder joint. Various animal models have been described for this condition, but all current translational animal models have inherent weaknesses in their ability to generate chronically degenerated rotator cuff tendons. The objective of this study was to evaluate a partial infraspinatus tendon transection model as a means of creating a chronically degenerated rotator cuff tendon in an ovine model and compare the injury characteristics of this model to those observed in human patients with severe chronic rotator cuff tendon injuries. STUDY DESIGN/METHODS: The infraspinatus tendons of six sheep were partially detached followed by capping of the detached medial section of the tendon with Gore-Tex. Human tissue samples of the supraspinatus tendon were harvested from patients undergoing primary reverse shoulder arthroplasty and served as positive controls of chronic rotator cuff tendinopathy. RESULTS: Transected sheep tendons were characterized predominantly by an acute reactive and reparative pathological process as compared with the chronic degenerative changes observed in the human tendons. In contrast, the non-transected portion of the ovine tendon showed histological changes, which were more chronic and degenerative in nature when compared with the transected tendon. CONCLUSION/CONCLUSIONS: Overall, histological features of the non-transected portion of ovine tendon were more similar to those observed in the chronic degenerated human tendon.

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

OBJECTIVE:demonstrated superior efficacy and comparable safety of fingolimod versus interferon β-1a (IFN β-1a) in paediatric-onset multiple sclerosis (PoMS). This study aimed to report all predefined MRI outcomes from this study. METHODS:Patients with multiple sclerosis (MS) (aged 10-<18 years) were randomised to once-daily oral fingolimod (n=107) or once-weekly intramuscular IFN β-1a (n=108) in this flexible duration study. MRI was performed at baseline and every 6 months for up to 2 years or end of the study (EOS) in case of early treatment discontinuation/completion. Key MRI endpoints included the annualised rate of formation of new/newly enlarging T2 lesions, gadolinium-enhancing (Gd+) T1 lesions, new T1 hypointense lesions and combined unique active (CUA) lesions (6 months onward), changes in T2 and Gd+ T1 lesion volumes and annualised rate of brain atrophy (ARBA). RESULTS:Of the randomised patients, 107 each were treated with fingolimod and IFN β-1a for up to 2 years. Fingolimod reduced the annualised rate of formation of new/newly enlarging T2 lesions (52.6%, p<0.001), number of Gd+ T1 lesions per scan (66.0%, p<0.001), annualised rate of new T1 hypointense lesions (62.8%, p<0.001) and CUA lesions per scan (60.7%, p<0.001) versus IFN β-1a at EOS. The percent increases from baseline in T2 (18.4% vs 32.4%, p<0.001) and Gd+ T1 (-72.3% vs 4.9%, p=0.001) lesion volumes and ARBA (-0.48% vs -0.80%, p=0.014) were lower with fingolimod versus IFN β-1a, the latter partially due to accelerated atrophy in the IFN β-1a group. CONCLUSION/CONCLUSIONS:Fingolimod significantly reduced MRI activity and ARBA for up to 2 years versus IFN β-1a in PoMS.

Non-steroidal anti-inflammatory drugs (NSAIDs), commonly known as COX-1/COX-2 inhibitors, can be effective in treating mild to moderate migraine headache. However, the mechanism by which these drugs act in migraine is not known, nor is the specific contribution of COX-1 versus COX-2 known. We sought to investigate these unknowns using celecoxib, which selectively inhibits the enzymatic activity of COX-2, by determining its effects on several migraine-associated vascular and inflammatory events. Using in vivo two-photon microscopy, we determined intraperitoneal celecoxib effects on CSD-induced blood vessel responses, plasma protein extravasation, and immune cell activation in the dura and pia of mice and rats. Compared to vehicle (control group), celecoxib reduced significantly CSD-induced dilatation of dural arteries and activation of dural and pial macrophages but not dilatation or constriction of pial arteries and veins, or the occurrence of plasma protein extravasation. Collectively, these findings suggest that a mechanism by which celecoxib-mediated COX-2 inhibition might ease the intensity of migraine headache and potentially terminate an attack is by attenuating dural macrophages activation and arterial dilatation outside the blood brain barrier (BBB), and pial macrophages activation inside the BBB.