Implementation and Follow-up Experience of an e-Consult Program in a Rural Neurology Setting.

OBJECTIVE: The demand for neurology services at Geisinger exceeds the current clinical capacity. Therefore, we implemented and assessed the utility of Ask-a-Doc (AAD), which is an electronic medical record-based interface developed at Geisinger to facilitate communication between primary care physicians (PCPs) and specialists. METHODS: AAD was used at the end of 2015 in our department. Based on the clinical picture, the PCP assesses whether to send an urgent AAD question with a phone request or a more elective question that can be answered by email message. The AAD message is then relayed to the on-call neurologist. We analyzed 4-year longitudinal data to assess for the efficacy of this tool in our department in improving patient care and communication. RESULTS: There were a total of 3,190 messages during this period. Of which, 2,927 (91.7%) were completed and routed correctly, and 263 (8.3%) messages had errors including routing issues, communication mismatch, and delayed time frame. The average specialist turnaround time was 5 hours. During this period, the number of AAD messages increased by 300% as PCPs and neurologists became more comfortable with the process. CONCLUSIONS: AAD provides an interface between PCPs and neurology specialists and can assist in determining whether a patient needs to be seen urgently in the clinic, the correct subspecialty, and prerequisite diagnostic tests. AAD was successfully implemented and used in our rural neurology setting, with rapid turnaround, increased usage, and accuracy.

Adherence to anticoagulant guideline for atrial fibrillation: A large care gap among stroke patients in a rural population.

OBJECTIVE: This study aimed to investigate the prevalence and factors associated with oral anticoagulant undertreatment of atrial fibrillation (AF) among a cohort of rural patients with stroke outcomes and examine how undertreatment may influence a patient's one-year survival after stroke. METHODS: This retrospective cohort study examined ischemic stroke patients with pre-stroke AF diagnosis from September 2003 to May 2019 and divided them into proper treatment and undertreatment group. Analysis included chi-square test, variance analysis, Kruskal-Wallis test, logistic regression, Kaplan-Meier estimator, and Cox proportional-hazards model. RESULTS: Out of 1062 ischemic stroke patients with a pre-stroke AF diagnosis, 1015 patients had a CHA2DS2-VASc score ≥2, and 532 (52.4%) of those were undertreated. Median time from AF diagnosis to index stroke was significantly lower among undertreated patients (1.9 years vs. 3.6 years, p < 0.001). Other thromboembolism, excluding stroke, TIA, and myocardial infarction (OR 0.41, p < 0.001), the number of encounters per year (OR 0.90, p < 0.001), and the median time between AF diagnosis and stroke event (OR 0.86, p < 0.001) were negatively associated with undertreatment. Kaplan-Meier estimator showed no statistical difference in the one-year survival probability between groups (log-rank test, p = 0.29), while the Cox-Hazard model showed that age (HR 1.05, p < 0.001) and history of congestive heart failure (HR 1.88, p < 0.001) increased the risk of mortality. CONCLUSIONS: More than half of our rural stroke patients with a pre-index AF diagnosis were not on guideline-recommended treatment. The study highlights a large care gap and an opportunity to improve AF management.

Cognitive Sequelae of Central-Variant Posterior Reversible Encephalopathy Syndrome (PRES).

INTRODUCTION: Although the posterior reversible encephalopathy syndrome (PRES) is often associated with headache and visual changes, central-variant PRES can be difficult to clinically diagnose in a patient with alteration of consciousness. Central-variant PRES has been previously described in the literature affecting subcortical white matter and the brainstem. Case Presentation. We describe a case presenting with hypertension (192/98) and altered level of consciousness requiring intubation. She was ultimately found to have extensive symmetric cortical and subcortical edema, with extensive involvement of bilateral thalami, consistent with central-variant PRES. Her mentation rapidly improved with blood pressure management. Confirmation of the diagnosis of central-variant PRES was made on repeat brain imaging. Our case is unique in demonstrating dramatic central white matter changes and their reversibility on repeat imaging six days later. Finally, persistent cognitive deficits at follow-up four months later are described. CONCLUSION: Atypical presentations of PRES, involving alterations in levels of consciousness, can be difficult to clinically diagnose. A thorough differential diagnosis is even more important in cases of PRES with atypical imaging. Recognition of the diagnostic patterns of PRES on brain imaging, with prompt reversal of the causative factors, is crucial for the appropriate care of these patients. The long-term sequelae, which could include cognitive deficits, are poorly studied and understood.

Serotonin Syndrome Presenting as a Posterior Reversible Encephalopathy Syndrome.

Posterior reversible encephalopathy syndrome (PRES) is a neurological syndrome characterized by an altered level of consciousness, headaches, seizure, and visual changes. PRES has several different etiologies, including malignant hypertension, eclampsia, and certain medications. Here, we describe a 41-year-old woman who presented with altered mental status. She had a preliminary diagnosis of serotonin syndrome as she was on many different serotonin-sparing agents, but her imaging findings were consistent with PRES. After her medications were reviewed and the causative agent was removed, the patient's neurological exam and imaging findings improved, and she returned to her baseline. To our knowledge, this is a unique case of PRES caused by serotonin syndrome secondary to venlafaxine usage.

IGFBPL1 Regulates Axon Growth through IGF-1-mediated Signaling Cascades.

Activation of axonal growth program is a critical step in successful optic nerve regeneration following injury. Yet the molecular mechanisms that orchestrate this developmental transition are not fully understood. Here we identified a novel regulator, insulin-like growth factor binding protein-like 1 (IGFBPL1), for the growth of retinal ganglion cell (RGC) axons. Expression of IGFBPL1 correlates with RGC axon growth in development, and acute knockdown of IGFBPL1 with shRNA or IGFBPL1 knockout in vivo impaired RGC axon growth. In contrast, administration of IGFBPL1 promoted axon growth. Moreover, IGFBPL1 bound to insulin-like growth factor 1 (IGF-1) and subsequently induced calcium signaling and mammalian target of rapamycin (mTOR) phosphorylation to stimulate axon elongation. Blockage of IGF-1 signaling abolished IGFBPL1-mediated axon growth, and vice versa, IGF-1 required the presence of IGFBPL1 to promote RGC axon growth. These data reveal a novel element in the control of RGC axon growth and suggest an unknown signaling loop in the regulation of the pleiotropic functions of IGF-1. They suggest new therapeutic target for promoting optic nerve and axon regeneration and repair of the central nervous system.

The association of adult vaccination with the risk of cerebrovascular ischemia: A systematic review and meta-analysis.

There is mounting evidence supporting infection as an independent risk factor for ischemic stroke (IS), while preliminary data indicate that vaccination may prevent IS. We performed a systematic review and meta-analysis of available randomized clinical trials (RCTs) or prospective observational cohorts reporting associations of influenza vaccination (IV) and/or pneumococcal vaccination (PV) with IS. We identified a total of 12 studies (543,311 patients; 47.4% vaccinated). Vaccination was not related to the risk of IS (RR=1.06, 95%CI: 0.74-1.51, p=0.77), with no significant differences (p=0.26) among RCTs (RR=0.66, 95%CI: 0.30-1.47) and observational studies (RR=1.11, 95%CI: 0.76-1.61). Evidence of considerable heterogeneity was identified within observational studies (I2=98%), but not within RCTs (I2=0%). In subgroup analyses according to vaccination type, IV was associated with a significantly lower risk of IS (RR=0.87, 95%CI: 0.79-0.96, p=0.004) with moderate evidence of heterogeneity (I2=53%). No association was seen for PV (RR=1.38, 95%CI: 0.60-3.16, p=0.45), where considerable heterogeneity was identified (I2=97%). In the additional adjusted analyses of observational studies, vaccination tended to be associated with lower risk of IS (HRadjusted=0.87; 95%CI: 0.75-1.01; p=0.07). The findings of this meta-analysis indicate that IV may be associated with a lower risk of IS. This association was not reproduced for PV or the combination of two vaccines. Substantial heterogeneity was detected across observational studies for all outcome events, while moderate to low heterogeneity was identified across included RCTs. These preliminary findings require independent validation in large RCTs.

The effect of alcohol and red wine consumption on clinical and MRI outcomes in multiple sclerosis.

BACKGROUND: Alcohol and in particular red wine have both immunomodulatory and neuroprotective properties, and may exert an effect on the disease course of multiple sclerosis (MS). OBJECTIVE: To assess the association between alcohol and red wine consumption and MS course. METHODS: MS patients enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB) who completed a self-administered questionnaire about their past year drinking habits at a single time point were included in the study. Alcohol and red wine consumption were measured as servings/week. The primary outcome was the Expanded Disability Status Scale (EDSS) at the time of the questionnaire. Secondary clinical outcomes were the Multiple Sclerosis Severity Score (MSSS) and number of relapses in the year before the questionnaire. Secondary MRI outcomes included brain parenchymal fraction and T2 hyperintense lesion volume (T2LV). Appropriate regression models were used to test the association of alcohol and red wine intake on clinical and MRI outcomes. All analyses were controlled for sex, age, body mass index, disease phenotype (relapsing vs. progressive), the proportion of time on disease modifying therapy during the previous year, smoking exposure, and disease duration. In the models for the MRI outcomes, analyses were also adjusted for acquisition protocol. RESULTS: 923 patients (74% females, mean age 47 ± 11 years, mean disease duration 14 ± 9 years) were included in the analysis. Compared to abstainers, patients drinking more than 4 drinks per week had a higher likelihood of a lower EDSS score (OR, 0.41; p = 0.0001) and lower MSSS (mean difference, - 1.753; p = 0.002) at the time of the questionnaire. Similarly, patients drinking more than 3 glasses of red wine per week had greater odds of a lower EDSS (OR, 0.49; p = 0.0005) and lower MSSS (mean difference, - 0.705; p = 0.0007) compared to nondrinkers. However, a faster increase in T2LV was observed in patients consuming 1-3 glasses of red wine per week compared to nondrinkers. CONCLUSIONS: Higher total alcohol and red wine intake were associated with a lower cross-sectional level of neurologic disability in MS patients but increased T2LV accumulation. Further studies should explore a potential cause-effect neuroprotective relationship, as well as the underlying biological mechanisms.

Lateral Medullary Ischemic Infarct Caused by Posterior Inferior Cerebellar Artery Aneurysm.

Posterior inferior cerebellar artery (PICA) aneurysms are rare. The most common complication of intracranial aneurysms is rupture causing subarachnoid hemorrhage. Ischemic infarct, although more common in giant thrombosed aneurysms, is a very rare manifestation of small intracranial aneurysms. Here we describe a patient who presented with lateral medullary acute infarction associated with an ipsilateral, small (4 × 3.5 mm), unruptured and non-thrombosed PICA aneurysm.

Recurrent Intracerebral Hemorrhage after Exercise in a Young Patient Presenting with Sporadic Cerebral Amyloid Angiopathy in a Young Patient.

Cerebral Amyloid Angiopathy (CAA) is one of the significant causes of lobar intracerebral hemorrhage (ICH) mainly among elderly people. Sporadic cases of CAA have been linked to genetic polymorphisms with an increased risk of disease, an earlier presentation, and an accelerated pathology [1]. Here, we present a patient with no significant risk factors who had a recurrent intracerebral hemorrhage secondary to CAA probably induced by exercise.

Postnatal onset of retinal degeneration by loss of embryonic Ezh2 repression of Six1.

Some adult-onset disorders may be linked to dysregulated embryonic development, yet the mechanisms underlying this association remain poorly understood. Congenital retinal degenerative diseases are blinding disorders characterized by postnatal degeneration of photoreceptors, and affect nearly 2 million individuals worldwide, but ∼50% do not have a known mutation, implicating contributions of epigenetic factors. We found that embryonic deletion of the histone methyltransferase (HMT) Ezh2 from all retinal progenitors resulted in progressive photoreceptor degeneration throughout postnatal life, via derepression of fetal expression of Six1 and its targets. Forced expression of Six1 in the postnatal retina was sufficient to induce photoreceptor degeneration. Ezh2, although enriched in the embryonic retina, was not present in the mature retina; these data reveal an Ezh2-mediated feed-forward pathway that is required for maintaining photoreceptor homeostasis in the adult and suggest novel targets for retinal degeneration therapy.

Factors associated with recovery from acute optic neuritis in patients with multiple sclerosis.

OBJECTIVE: To identify clinical and demographic features associated with the severity and recovery from acute optic neuritis (AON) episodes in patients with multiple sclerosis (MS). METHODS: Adult (n = 253) and pediatric (n = 38) patients whose first symptom was AON were identified from our MS database. Severity measured by loss of visual acuity (mild attack ≤20/40, moderate attack 20/50-20/190, and severe attack ≥20/200) and recovery in visual acuity at 1 year after the attack (complete recovery ≤20/20, fair recovery 20/40, and poor recovery ≥20/50) were recorded. Demographic and clinical features associated with attack severity and recovery were identified using proportional odds logistic regression. For another group of patients, blood samples were available within 6 months of an AON attack. In this group, the impact of vitamin D level on the severity/recovery was also assessed. RESULTS: Men (adjusted odds ratio [OR] = 2.28, p = 0.03) and subjects with severe attacks (adjusted OR = 5.24, p < 0.001) had worse recovery. AON severity was similar between the pediatric and adult subjects, but recovery was significantly better in pediatric subjects in the unadjusted analysis (p = 0.041) and the analysis adjusted for sex (p = 0.029). Season-adjusted vitamin D level was significantly associated with attack severity (OR for 10-U increase in vitamin D level = 0.47; 95% confidence interval: 0.32, 0.68; p < 0.001). Vitamin D level was not associated with recovery from the attack (p = 0.98) in univariate analysis or after accounting for attack severity (p = 0.10). CONCLUSION: Vitamin D levels affect AON severity, whereas younger age, attack severity, and male sex affect AON recovery. Underlying mechanisms and potential therapeutic targets may identify new measures to mitigate disability accrual in MS.

Neuroglobin is an endogenous neuroprotectant for retinal ganglion cells against glaucomatous damage.

Neuroglobin (NGB), a newly discovered member of the globin superfamily, may regulate neuronal survival under hypoxia or oxidative stress. Although NGB is greatly expressed in retinal neurons, the biological functions of NGB in retinal diseases remain largely unknown. We investigated the role of NGB in an experimental model of glaucoma, a neurodegenerative disorder that usually involves elevation of intraocular pressure (IOP). Elevated IOP is thought to induce oxidative stress in retinal ganglion cells (RGCs), thereby causing RGC death and, eventually, blindness. We found that NGB plays a critical role in increasing RGC resistance to ocular hypertension and glaucomatous damage. Elevation of IOP stimulated a transient up-regulation of endogenous NGB in RGCs. Constitutive overexpression of NGB in transgenic mice prevented RGC damage induced by glutamate cytotoxicity in vitro and/or by chronic IOP elevation in vivo. Moreover, overexpression of NGB attenuated ocular hypertension-induced superoxide production and the associated decrease in ATP levels in mice, suggesting that NGB acts as an endogenous neuroprotectant to reduce oxidative stress and improve mitochondrial function, thereby promoting RGC survival. Thus, NGB may modulate RGC susceptibility to glaucomatous neural damage. Manipulating the expression and bioactivity of NGB may represent a novel therapeutic strategy for glaucoma.

Dynamic patterns of histone lysine methylation in the developing retina.

PURPOSE: Histone lysine methylation (HKM) is an important epigenetic mechanism that establishes cell-specific gene expression and functions in development. However, epigenetic control of retinal development is poorly understood. To study the roles of HKM in retinogenesis, the authors examined the dynamic changes of three HKM modifications and of two of their regulators, the histone methyltransferases (HMTases) Ezh2 and G9a, in the mouse retina. METHODS: Retinal sections and lysates from embryonic day 16 through adult were processed for immunohistochemistry and immunoblotting using antibodies against various marks and HMTases. To further analyze the biological functions of HKM, the effects of small molecule inhibitors of HMTases were examined in vitro. RESULTS: Methylation marks of trimethyl lysine 4 and 27 on histone H3 (H3K4me3 and H3K27me3) were detected primarily in differentiated retinal neurons in the embryonic and adult retina. In contrast, dimethyl lysine 9 on histone H3 (H3K9me2) was noted in early differentiating retinal ganglion cells but was lost after birth. The HMTases controlling H3K27me3, H3K9me2, Ezh2, and G9a were enriched in the inner embryonic retina during the period of active retinogenesis. Using the chemical inhibitors of Ezh2 and G9a, the authors reveal a role for HKM in regulating retinal neuron survival. CONCLUSIONS: HKM is a dynamic and spatiotemporally regulated process in the developing retina. Epigenetic regulation of gene transcription by Ezh2- and G9a-mediated HKM plays crucial roles in retinal neuron survival and may represent novel epigenetic targets to enhance viability in retinal neurodegenerative diseases such as glaucoma.