Faculty Bibliography

This is a patient with multiple meningoencephaloceles which resulted in bacterial meningitis and subsequent status epilepticus. We identify impressive imaging findings demonstrating herniation of the meninges from nasal and bitemporal skull base defects possibly as a result of intracranial hypertension.

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.

INTRODUCTION/BACKGROUND:We tested the hypothesis that functional limb weakness is associated with possible dysfunction of the central processing of proprioceptive information, by evaluating the amount of tonic vibration reflex (TVR) and the perception of the TVR movement. METHODS:The study sample was 20 patients with functional weakness of the lower and/or the upper limbs and 25 healthy controls; delivery of 92-Hz transcutaneous vibration of the biceps brachii tendon of the unrestrained arm stimulated predominantly the muscle spindle afferent and elicited elbow flexion (tonic vibration reflex, TVR). Blindfolded participants had to match the final position of the vibrated arm with their contralateral tracking arm. The TVR and perception of the TVR movement were measured as angle movements of the vibrated arm and the tracking arm, respectively. RESULTS:The magnitude of the TVR of the vibrated arm and movement perception of the TVR of the tracking arm were significantly reduced in the patients compared to the controls. No correlation was found between magnitude of the TVR and perception of the TVR movement, suggesting that the abnormalities were independent of each other. Moreover, the abnormalities did not differ between the patients with/without bilateral upper limb involvement or between the affected and the unaffected side in patients with unilateral impairment, suggesting that the observed deficits are independent of motor impairment. CONCLUSIONS:Proprioceptive dysfunction may underlie alterations in body movement and in sense of agency in such patients and may play a role in the pathophysiology of functional limb weakness.

The pathological cascade of tissue damage in mild traumatic brain injury is set forth by a perturbation in ionic homeostasis. However, whether this class of injury can be detected in vivo and serve as a surrogate marker of clinical outcome is unknown. We employ sodium MRI to test the hypotheses that regional and global total sodium concentrations: (i) are higher in patients than in controls and (ii) correlate with clinical presentation and neuropsychological function. Given the novelty of sodium imaging in traumatic brain injury, effect sizes from (i), and correlation types and strength from (ii), were compared to those obtained using standard diffusion imaging metrics. Twenty-seven patients (20 female, age 35.9 ± 12.2 years) within 2 months after injury and 19 controls were scanned with proton and sodium MRI at 3 Tesla. Total sodium concentration, fractional anisotropy and apparent diffusion coefficient were obtained with voxel averaging across 12 grey and white matter regions. Linear regression was used to obtain global grey and white matter total sodium concentrations. Patient outcome was assessed with global functioning, symptom profiles and neuropsychological function assessments. In the regional analysis, there were no statistically significant differences between patients and controls in apparent diffusion coefficient, while differences in sodium concentration and fractional anisotropy were found only in single regions. However, for each of the 12 regions, sodium concentration effect sizes were uni-directional, due to lower mean sodium concentration in patients compared to controls. Consequently, linear regression analysis found statistically significant lower global grey and white matter sodium concentrations in patients compared to controls. The strongest correlation with outcome was between global grey matter sodium concentration and the composite z-score from the neuropsychological testing. In conclusion, both sodium concentration and diffusion showed poor utility in differentiating patients from controls, and weak correlations with clinical presentation, when using a region-based approach. In contrast, sodium linear regression, capitalizing on partial volume correction and high sensitivity to global changes, revealed high effect sizes and associations with patient outcome. This suggests that well-recognized sodium imbalances in traumatic brain injury are (i) detectable non-invasively; (ii) non-focal; (iii) occur even when the antecedent injury is clinically mild. Finally, in contrast to our principle hypothesis, patients' sodium concentrations were lower than controls, indicating that the biological effect of traumatic brain injury on the sodium homeostasis may differ from that in other neurological disorders. Note: This figure has been annotated.

BACKGROUND AND PURPOSE/OBJECTIVE:In symptomatic intracranial atherosclerotic stenosis (ICAS), borderzone infarct pattern and perfusion mismatch are associated with increased risk of recurrent strokes, which may reflect the shared underlying mechanism of hypoperfusion distal to the intracranial atherosclerosis. Accordingly, we hypothesized a correlation between hypoperfusion volumes and ICAS infarct patterns based on the respective underlying mechanistic subtypes. METHODS:We conducted a retrospective analysis of consecutive symptomatic ICAS cases, acute strokes due to subocclusive (50%-99%) intracranial stenosis. The following mechanistic subtypes were assigned based on the infarct pattern on the diffusion-weighted imaging: Branch occlusive disease (BOD), internal borderzone (IBZ), and thromboembolic (TE). Perfusion parameters, obtained concurrently with the MRI, were studied in each group. RESULTS: > 6 s) was substantially greater. CONCLUSION/CONCLUSIONS:ICAS infarct patterns, in keeping with their respective underlying mechanisms, may correlate with distinct perfusion profiles.

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.

BACKGROUND AND PURPOSE/OBJECTIVE:A subset of ischaemic stroke patients with atrial fibrillation (AF) have ischaemic stroke despite anticoagulation. We sought to determine the association between prestroke anticoagulant therapy and recurrent ischaemic events and symptomatic intracranial haemorrhage (sICH). METHODS:We included consecutive patients with acute ischaemic stroke and AF from the Initiation of Anticoagulation after Cardioembolic stroke (IAC) study from eight comprehensive stroke centres in the USA. We compared recurrent ischaemic events and delayed sICH risk using adjusted Cox regression analyses between patients who were prescribed anticoagulation (ACp) versus patients who were naïve to anticoagulation therapy prior to the ischaemic stroke (anticoagulation naïve). RESULTS:Among 2084 patients in IAC, 1518 had prior anticoagulation status recorded and were followed for 90 days. In adjusted Cox hazard models, ACp was associated with some evidence of a higher risk higher risk of 90-day recurrent ischaemic events only in the fully adjusted model (adjusted HR 1.50, 95% CI 0.99 to 2.28, p=0.058) but not increased risk of 90-day sICH (adjusted HR 1.08, 95% CI 0.46 to 2.51, p=0.862). In addition, switching anticoagulation class was not associated with reduced risk of recurrent ischaemic events (adjusted HR 0.41, 95% CI 0.12 to 1.33, p=0.136) nor sICH (adjusted HR 1.47, 95% CI 0.29 to 7.50, p=0.641). CONCLUSION/CONCLUSIONS:AF patients with ischaemic stroke despite anticoagulation may have higher recurrent ischaemic event risk compared with anticoagulation-naïve patients. This suggests differing underlying pathomechanisms requiring different stroke prevention measures and identifying these mechanisms may improve secondary prevention strategies.

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.

OBJECTIVE:To determine changes in clinical features and striatal dopamine reuptake transporter (DAT) density after shunt surgery in patients with idiopathic normal pressure hydrocephalus (iNPH). METHODS:I]-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane (FP-CIT). Levodopa responsiveness was also evaluated. Patients who did or did not undergo lumboperitoneal shunt were clinically followed up and repeated SPECT after 2 years. RESULTS:< 0.01). CONCLUSIONS:This prospective interventional study highlights the pathophysiological relevance of striatal dopaminergic dysfunction in the motor phenotypic expression of iNPH. Absence of levodopa responsiveness, shunt-responsive parkinsonism, and post-surgery improvement of striatal DAT density are findings that corroborate the notion of a reversible striatal dysfunction in a subset of iNPH patients.

Objective. Large channel count surface-based electrophysiology arrays (e.g. µECoG) are high-throughput neural interfaces with good chronic stability. Electrode spacing remains ad hoc due to redundancy and nonstationarity of field dynamics. Here, we establish a criterion for electrode spacing based on the expected accuracy of predicting unsampled field potential from sampled sites.Approach. We applied spatial covariance modeling and field prediction techniques based on geospatial kriging to quantify sufficient sampling for thousands of 500 ms µECoG snapshots in human, monkey, and rat. We calculated a probably approximately correct (PAC) spacing based on kriging that would be required to predict µECoG fields at≤10% error for most cases (95% of observations).Main results. Kriging theory accurately explained the competing effects of electrode density and noise on predicting field potential. Across five frequency bands from 4-7 to 75-300 Hz, PAC spacing was sub-millimeter for auditory cortex in anesthetized and awake rats, and posterior superior temporal gyrus in anesthetized human. At 75-300 Hz, sub-millimeter PAC spacing was required in all species and cortical areas.Significance. PAC spacing accounted for the effect of signal-to-noise on prediction quality and was sensitive to the full distribution of non-stationary covariance states. Our results show that µECoG arrays should sample at sub-millimeter resolution for applications in diverse cortical areas and for noise resilience.