Faculty Bibliography

Objectives The occurrence of head computed tomography (HCT) at emergency department (ED) visit for non-specific neurological symptoms has been associated with increased subsequent stroke risk and may be a marker of diagnostic error. We evaluate whether HCT occurrence among ED headache patients is associated with increased subsequent cerebrovascular disease risk. Methods We conducted a retrospective cohort study of consecutive adult patients with headache who were discharged home from the ED (ED treat-and-release visit) at one multicenter institution. Patients with headache were defined as those with primary ICD-9/10-CM discharge diagnoses codes for benign headache from 9/1/2013-9/1/2018. The primary outcome of cerebrovascular disease hospitalization was identified using ICD-9/10-CM codes and confirmed via chart review. We matched headache patients who had a HCT (exposed) to those who did not have a HCT (unexposed) in the ED in a one-to-one fashion using propensity score methods. Results Among the 28,121 adult patients with ED treat-and-release headache visit, 45.6% (n=12,811) underwent HCT. A total of 0.4% (n=111) had a cerebrovascular hospitalization within 365 days of index visit. Using propensity score matching, 80.4% (n=10,296) of exposed patients were matched to unexposed. Exposed patients had increased risk of cerebrovascular hospitalization at 365 days (RR: 1.65: 95% CI: 1.18-2.31) and 180 days (RR: 1.62; 95% CI: 1.06-2.49); risk of cerebrovascular hospitalization was not increased at 90 or 30 days. Conclusions Having a HCT performed at ED treat-and-release headache visit is associated with increased risk of subsequent cerebrovascular disease. Future work to improve cerebrovascular disease prevention strategies in this subset of headache patients is warranted.

Lacunar stroke is a marker of cerebral small vessel disease and accounts for up to 25% of ischaemic stroke. In this narrative review, we provide an overview of potential lacunar stroke mechanisms and discuss therapeutic implications based on the underlying mechanism. For this paper, we reviewed the literature from important studies (randomised trials, exploratory comparative studies and case series) on lacunar stroke patients with a focus on more recent studies highlighting mechanisms and stroke prevention strategies in patients with lacunar stroke. These studies suggest that lacunar stroke is a heterogeneous disease with various mechanisms, including most commonly lipohyalinosis and less commonly atheromatous disease and cardioembolism, highlighting the importance of a careful review of brain and neurovascular imaging, a cardiac and systemic evaluation. A better understanding of pathomechanisms of neurological deterioration may lead to investigating the utility of novel treatment strategies and optimisation of short-term antithrombotic treatment strategies to reduce the risk of neurological deterioration and prevent long-term disability in patients with lacunar stroke.

OBJECTIVE:To develop and validate a tool for individualised prediction of Sudden Unexpected Death in Epilepsy (SUDEP) risk, we re-analysed data from one cohort and three case-control studies undertaken 1980-2005. METHODS:We entered 1273 epilepsy cases (287 SUDEP, 986 controls) and 22 clinical predictor variables into a Bayesian logistic regression model. RESULTS:Cross-validated individualized model predictions were superior to baseline models developed from only average population risk or from generalised tonic-clonic seizure frequency (pairwise difference in leave-one-subject-out expected log posterior density = 35.9, SEM +/-12.5, and 22.9, SEM +/-11.0 respectively). The mean cross-validated (95% Credibility Interval) Area Under the Receiver Operating Curve was 0.71 (0.68 to 0.74) for our model versus 0.38 (0.33 to 0.42) and 0.63 (0.59 to 0.67) for the baseline average and generalised tonic-clonic seizure frequency models respectively. Model performance was weaker when applied to non-represented populations. Prognostic factors included generalized tonic-clonic and focal-onset seizure frequency, alcohol excess, younger age of epilepsy onset and family history of epilepsy. Anti-seizure medication adherence was associated with lower risk. CONCLUSIONS:Even when generalised to unseen data, model predictions are more accurate than population-based estimates of SUDEP. Our tool can enable risk-based stratification for biomarker discovery and interventional trials. With further validation in unrepresented populations it may be suitable for routine individualized clinical decision-making. Clinicians should consider assessment of multiple risk factors, and not only focus on the frequency of convulsions.

OBJECTIVE:To identify the molecular signaling pathways underlying sudden unexpected death in epilepsy (SUDEP) and high-risk SUDEP compared to epilepsy control patients. METHODS:For proteomics analyses, we evaluated the hippocampus and frontal cortex from microdissected post-mortem brain tissue of 12 SUDEP and 14 non-SUDEP epilepsy patients. For transcriptomics analyses, we evaluated hippocampus and temporal cortex surgical brain tissue from mesial temporal lobe epilepsy (MTLE) patients: 6 low-risk and 8 high-risk SUDEP as determined by a short (< 50 seconds) or prolonged (≥ 50 seconds) postictal generalized EEG suppression (PGES) that may indicate severely depressed brain activity impairing respiration, arousal, and protective reflexes. RESULTS:In autopsy hippocampus and cortex, we observed no proteomic differences between SUDEP and non-SUDEP epilepsy patients, contrasting with our previously reported robust differences between epilepsy and non-epilepsy control patients. Transcriptomics in hippocampus and cortex from surgical epilepsy patients segregated by PGES identified 55 differentially expressed genes (37 protein-coding, 15 lncRNAs, three pending) in hippocampus. CONCLUSION/CONCLUSIONS:The SUDEP proteome and high-risk SUDEP transcriptome were similar to other epilepsy patients in hippocampus and frontal cortex, consistent with diverse epilepsy syndromes and comorbidities associated with SUDEP. Studies with larger cohorts and different epilepsy syndromes, as well as additional anatomic regions may identify molecular mechanisms of SUDEP.

Proteogenomics is an increasingly common method for species identification as it allows for rapid and inexpensive interrogation of an unknown organism's proteome-even when the proteome is partially degraded. The proteomic method typically uses tandem mass spectrometry to survey all peptides detectable in a sample that frequently contains hundreds or thousands of proteins. Species identification is based on detection of a small numbers of species-specific peptides. Genetic analysis of proteins by mass spectrometry, however, is a developing field, and the bone proteome, typically consisting of only two proteins, pushes the limits of this technology. Nearly 20% of highly confident spectra from modern human bone samples identify non-human species when searched against a vertebrate database-as would be necessary with a fragment of unknown bone. These non-human peptides are often the result of current limitations in mass spectrometry or algorithm interpretation errors. Consequently, it is difficult to know if a "species-specific" peptide used to identify a sample is actually present in that sample. Here we evaluate the causes of peptide sequence errors and propose an unbiased, probabilistic approach to determine the likelihood that a species is correctly identified from bone without relying on species-specific peptides.

Venous variants and pathologic abnormalities are the most common causes of pulsatile tinnitus. These conditions include causes of turbulence within normally located veins and sinuses, and abnormally enlarged or abnormally located veins in close transmissive proximity to the conductive auditory pathway. Such disorders include pathologic abnormalities of the lateral sinus (transverse sinus stenosis and sigmoid sinus wall anomalies), abnormalities and variants of the emissary veins, and anomalies of the jugular bulb and jugular vein. Despite being the most common causes for pulsatile tinnitus, venous variants and pathologic abnormalities are often overlooked in the workup of pulsatile tinnitus. Such oversights can result in delayed patient care and prolonged patient discomfort. Advances in both cerebrovascular imaging and endovascular techniques allow for improved diagnostic accuracy and an increasing range of endovascular therapeutic options to address pulsatile tinnitus. This review illustrates the venous causes of pulsatile tinnitus and demonstrates the associated endovascular treatment. © RSNA, 2021.

Images of DaTscan (ioflupane [123I] SPECT) have been used as an adjunct to clinical diagnosis to facilitate the differential diagnosis of neurodegenerative (ND) Parkinsonian Syndrome (PS) vs. non-dopamine deficiency aetiologies of Parkinsonism. Despite several systematic reviews having summarised the evidence on diagnostic accuracy, the impact of imaging results on clinical utility has not been systematically assessed. Our objective was to examine the available evidence on the clinical utility of DaTscan imaging in changing diagnosis and subsequent management of patients with suspected PS. We performed a systematic review of published studies of clinical utility from 2000 to 2019 without language restrictions. A meta-analysis of change in diagnosis and management rates reported from each study was performed using a random-effects model and logit transformation. Sub-group analysis, meta-regression and sensitivity analysis was performed to explore heterogeneity. Twenty studies met the inclusion criteria. Thirteen of these contributed to the meta-analyses including 950 and 779 patients with a reported change in management and change in diagnosis, respectively. The use of DaTscan imaging resulted in a change in management in 54% (95% CI: 47-61%) of patients. Change in diagnosis occurred in 31% (95% CI: 22-42%) of patients. The two pooled analyses were characterised by high levels of heterogeneity. Our systematic review and meta-analysis show that imaging with DaTscan was associated with a change in management in approximately half the patients tested and the diagnosis was modified in one third. Regardless of time from symptom onset to scan results, these changes were consistent. Further research focusing on specific patient subgroups could provide additional evidence on the impact on clinical outcomes.

Parkinson's disease medication treatment planning is generally based on subjective data obtained through clinical, physician-patient interactions. The Personal KinetiGraphâ„¢ (PKG) and similar wearable sensors have shown promise in enabling objective, continuous remote health monitoring for Parkinson's patients. In this proof-of-concept study, we propose to use objective sensor data from the PKG and apply machine learning to cluster patients based on levodopa regimens and response. The resulting clusters are then used to enhance treatment planning by providing improved initial treatment estimates to supplement a physician's initial assessment. We apply k-means clustering to a dataset of within-subject Parkinson's medication changes-clinically assessed by the MDS-Unified Parkinson's Disease Rating Scale-III (MDS-UPDRS-III) and the PKG sensor for movement staging. A random forest classification model was then used to predict patients' cluster allocation based on their respective demographic information, MDS-UPDRS-III scores, and PKG time-series data. Clinically relevant clusters were partitioned by levodopa dose, medication administration frequency, and total levodopa equivalent daily dose-with the PKG providing similar symptomatic assessments to physician MDS-UPDRS-III scores. A random forest classifier trained on demographic information, MDS-UPDRS-III scores, and PKG time-series data was able to accurately classify subjects of the two most demographically similar clusters with an accuracy of 86.9%, an F1 score of 90.7%, and an AUC of 0.871. A model that relied solely on demographic information and PKG time-series data provided the next best performance with an accuracy of 83.8%, an F1 score of 88.5%, and an AUC of 0.831, hence further enabling fully remote assessments. These computational methods demonstrate the feasibility of using sensor-based data to cluster patients based on their medication responses with further potential to assist with medication recommendations.

PURPOSE OF REVIEW:The newer, higher-efficacy disease-modifying therapies (DMTs) for multiple sclerosis (MS)-orals and monoclonals-have more profound immunomodulatory and immunosuppressive properties than the older, injectable therapies and require risk mitigation strategies to reduce the risk of serious infections. This review will provide a systematic framework for infectious risk mitigation strategies relevant to these therapies. RECENT FINDINGS:We classify risk mitigation strategies according to the following framework: (1) screening and patient selection, (2) vaccinations, (3) antibiotic prophylaxis, (4) laboratory and MRI monitoring, (5) adjusting dose and frequency of DMT, and (6) behavioral modifications to limit the risk of infection. We systematically apply this framework to the infections for which risk mitigations are available: hepatitis B, herpetic infections, progressive multifocal leukoencephalopathy, and tuberculosis. We also discuss up-to-date recommendations regarding COVID-19 vaccinations for patients on DMTs. We offer a practical, comprehensive, DMT-specific framework of derisking strategies designed to minimize the risk of infections associated with the newer MS therapies.

INTRODUCTION/UNASSIGNED:Although in some countries, palliative care (PC) still remains poorly implemented, its importance throughout the course of Parkinson's disease (PD) is increasingly being acknowledged. With an emergence of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pandemic, growing emphasis has been placed on the palliative needs of people with Parkinson's (PwP), particularly elderly, frail, and with comorbidities. AREAS COVERED/UNASSIGNED:The ongoing COVID-19 pandemic poses an enormous challenge on aspects of daily living in PwP and might interact negatively with a range of motor and non-motor symptoms (NMS), both directly and indirectly - as a consequence of pandemic-related social and health care restrictions. Here, the authors outline some of the motor and NMS relevant to PC, and propose a pragmatic and rapidly deployable, consensus-based PC approach for PwP during the ongoing COVID-19 pandemic, potentially relevant also for future pandemics. EXPERT OPINION/UNASSIGNED:The ongoing COVID-19 pandemic poses a considerable impact on PwP and their caregivers, ranging from mental health issues to worsening of physical symptoms - both in the short and long term ("Long-COVID"), and calls for specific personalized PC strategies relevant in a lockdown setting globally. Validated assessment tools should be applied remotely to flag up particular motor or NMS that require special attention, both in short- and long-term.