Faculty Bibliography

OBJECTIVE:To examine 36-month effects of bilateral subthalamic nucleus deep brain stimulation (STN-DBS) on non-motor symptoms (NMS) compared with standard-of-care medical treatment (MED) in Parkinson's disease (PD). METHODS:Here we report the 36-month follow-up of a prospective, observational, controlled, international multicentre study of the NILS cohort. Assessments included NMSScale (NMSS), PDQuestionnaire-8 (PDQ-8), Scales for Outcomes in PD (SCOPA)-motor examination, -activities of daily living, and -complications, and levodopa equivalent daily dose (LEDD). Propensity score matching resulted in a pseudo-randomised sub-cohort balancing baseline demographic and clinical characteristics between the STN-DBS and MED groups. Within-group longitudinal outcome changes were analysed using Wilcoxon signed-rank and between-group differences of change scores with Mann-Whitney U test. Strength of clinical responses was quantified with Cohen's effect size. In addition, bivariate correlations of change scores were explored. RESULTS:Propensity score matching applied on the cohort of 151 patients (STN-DBS n=67, MED n=84) resulted in a well-balanced sub-cohort including 38 patients per group. After 36 months, STN-DBS significantly improved NMSS, PDQ-8, SCOPA-motor examination and -complications and reduced LEDD. Significant between-group differences, all favouring STN-DBS, were found for NMSS, SCOPA-motor complications, LEDD (large effects), motor examination and PDQ-8 (moderate effects). Furthermore, significant differences were found for the sleep/fatigue, urinary (large effects) and miscellaneous NMSS domains (moderate effects). NMSS total and PDQ-8 change scores correlated significantly. CONCLUSIONS:This study provides Class IIb evidence for beneficial effects of STN-DBS on NMS at 36-month follow-up which also correlated with quality of life improvements. This highlights the importance of NMS for DBS outcomes assessments.

Early-phase clinical trials using oral inhibitors of MEK, the mitogen-activated protein kinase kinase, have demonstrated benefit for patients with neurofibromatosis type 1 (NF1)-associated tumors, particularly progressive low-grade gliomas and plexiform neurofibromas. Given this potential of MEK inhibition as an effective medical therapy, the use of targeted agents in the NF1 population is likely to increase substantially. For clinicians with limited experience prescribing MEK inhibitors, concern about managing these treatments may be a barrier to use. In this manuscript, the Clinical Care Advisory Board of the Children's Tumor Foundation reviews the published experience with MEK inhibitors in NF1 and outlines recommendations for side-effect management, as well as monitoring guidelines. These recommendations can serve as a beginning framework for NF providers seeking to provide the most effective treatments for their patients. IMPLICATIONS FOR PRACTICE: Neurofibromatosis type 1 (NF1) clinical care is on the cusp of a transformative shift. With the success of recent clinical trials using MEK inhibitors, an increasing number of NF1 patients are being treated with MEK inhibitors for both plexiform neurofibromas and low-grade gliomas. The use of MEK inhibitors is likely to increase substantially with the expected upcoming approval of selumetinib for a specific indication for treatment of plexiform neurofibromas in NF1. Given these changes, the Clinical Care Advisory Board of the Children's Tumor Foundation has identified a need within the NF1 clinical community for guidance for the safe and effective use of MEK inhibitors for NF1-related tumors. This article provides a review of the published experience of MEK inhibitors in NF1 and provides recommendations for monitoring and management of side effects.

BACKGROUND:Many headache smartphone applications (apps) are commercially available. A Modified Delphi Study aimed to determine specialists' expectations of what a headache app should entail but consumer expectations of headache apps have not been evaluated extensively. OBJECTIVE:To evaluate publicly available reviews of headache apps to understand app features that motivate the consumers to use apps. METHODS:The Google Play and Apple App Stores were systematically searched for headache/migraine diary apps with 10+ consumer reviews. A maximum of 300 "Most Helpful" reviews for each app were extracted. Four coders coded reviews and resolved discrepancies. Themes and subthemes were created based on codes used 5+ times. RESULTS:About 15 apps met the study criteria (9 Android, 6 IOS). 945 reviews were coded. Four themes emerged: (1) App allows users to track headache characteristics, potential triggers, and treatments; (2) App usability; (3) Personalization and features to assess trends in data are key motivators for app use; (4) Ease with exportation and viewing data is critical. DISCUSSION/CONCLUSIONS:A user-centered design with the ability to (1) customize key features including headache characteristics, potential triggers, and treatments, (2) assess trends in data, and (3) view and export data would best optimize headache smartphone applications based on consumer preference.

Cytokines were the first modern immunotherapies to produce durable responses in patients with advanced cancer, but they have only modest efficacy and limited tolerability^1,2. In an effort to identify alternative cytokine pathways for immunotherapy, we found that components of the interleukin-18 (IL-18) pathway are upregulated on tumour-infiltrating lymphocytes, suggesting that IL-18 therapy could enhance anti-tumour immunity. However, recombinant IL-18 previously did not demonstrate efficacy in clinical trials³. Here we show that IL-18BP, a high-affinity IL-18 decoy receptor, is frequently upregulated in diverse human and mouse tumours and limits the anti-tumour activity of IL-18 in mice. Using directed evolution, we engineered a 'decoy-resistant' IL-18 (DR-18) that maintains signalling potential but is impervious to inhibition by IL-18BP. Unlike wild-type IL-18, DR-18 exerted potent anti-tumour effects in mouse tumour models by promoting the development of poly-functional effector CD8⁺ T cells, decreasing the prevalence of exhausted CD8⁺ T cells that express the transcriptional regulator of exhaustion TOX, and expanding the pool of stem-like TCF1⁺ precursor CD8⁺ T cells. DR-18 also enhanced the activity and maturation of natural killer cells to effectively treat anti-PD-1 resistant tumours that have lost surface expression of major histocompatibility complex class I molecules. These results highlight the potential of the IL-18 pathway for immunotherapeutic intervention and implicate IL-18BP as a major therapeutic barrier.

OBJECTIVE:Middle meningeal artery (MMA) embolization may be an effective means of inhibiting neovascularization of the subdural capsular membrane and preventing hematoma maintenance. We sought to better understand how the MMA may affect subdural hematoma physiology and how this process may be modified by embolization. METHODS:A retrospective review was done. We studied 27 patients with 29 SDHs who underwent MMA embolization from July 2018 to May 2019. Eight of these patients had post-embolization DynaCT imaging and were included. RESULTS:Average patient age was 75 years old. Baseline non-contrast head CT showed the presence of a hematoma membrane in all 8 patients. Post-embolization DynaCTs in all patients demonstrated enhancement of all four components (dura, capsular membrane, septations, and subdural hematoma fluid). All patients had a minimum 60-day imaging and clinical follow-up. There was an average 87% decrease in SDH volume at last follow-up compared to baseline. There was a significant difference between the average baseline and average last follow-up SDH volume (paired t-test, p < 0.0001) in all patients. Average last follow-up scan was 89 days (range 61-122 days) from the date of procedure. No patient experienced post-embolization complications, subsequent SDH drainage, or mortality. CONCLUSIONS:Our data lends support to the theory of contiguous vascular networks between the MMA and SDH membranes. Targeting these leaky vascular networks may remove the source of hematoma accumulation. This adds to the pathophysiological understanding of the disease and suggests potential insight into the mechanism of action of MMA embolization.

BACKGROUND AND PURPOSE/OBJECTIVE:Efficacy of restorative cognitive rehabilitation can be predicted from baseline patient factors. In addition, patient profiles of functional connectivity are associated with cognitive reserve and moderate the structure-cognition relationship in people with multiple sclerosis (PwMS). Such interactions may help predict which PwMS will benefit most from cognitive rehabilitation. Our objective was to determine whether patient response to restorative cognitive rehabilitation is predictable from baseline structural network disruption and whether this relationship is moderated by functional connectivity. METHODS:For this single-arm repeated measures study, we recruited 25 PwMS for a 12-week program. Following magnetic resonance imaging, participants were tested using the Symbol Digit Modalities Test (SDMT) pre- and postrehabilitation. Baseline patterns of structural and functional connectivity were characterized relative to healthy controls. RESULTS:= .385, P = .017, Interaction β = -.415). CONCLUSION/CONCLUSIONS:Patient response to restorative cognitive rehabilitation is predictable from the interaction between structural network disruption and functional connectivity in the default-mode network. This effect may be related to cognitive reserve.

BACKGROUND AND PURPOSE/OBJECTIVE:Central retinal artery occlusion results in sudden, painless, usually permanent loss of vision in the affected eye. There is no proven, effective treatment to salvage visual acuity and a clear, unmet need for an effective therapy. In this work, we evaluated the efficacy of intravenous tissue-type plasminogen activator (IV alteplase) in a prospective cohort study and an updated systematic review and meta-analysis. METHODS:We enrolled consecutive patients with acute central retinal artery occlusion within 48 hours of symptoms onset and with a visual acuity of <20/200 from January 2009 until May 2019. The primary outcomes were safety and functional visual acuity recovery. We compared rates of visual recovery between those treated with alteplase within 4.5 hours of symptom onset to those who did not receive alteplase (including an analysis restricted to untreated patients presenting within the window for treatment). We incorporated these results into an updated systematic review and patient-level meta-analysis. RESULTS:=0.01). CONCLUSIONS:This study showed that the administration of intravenous alteplase within 4.5 hours of symptom onset is associated with a higher likelihood of a favorable visual outcome for acute central retinal artery occlusion. Our results strongly support proceeding to a randomized, placebo-controlled clinical trial.

INTRODUCTION:Embedded performance validity tests (PVTs) allow for continuous and economical validity assessment during neuropsychological evaluations; however, similar to their freestanding counterparts, a limitation of well-validated embedded PVTs is that the majority are memory-based. This study cross-validated several previously identified non-memory-based PVTs derived from language, processing speed, and executive functioning tests within a single mixed clinical neuropsychiatric sample with and without cognitive impairment. METHOD:This cross-sectional study included data from 124 clinical patients who underwent outpatient neuropsychological evaluation. Validity groups were determined by four independent criterion PVTs (failing ≤1 or ≥2), resulting in 98 valid (68% cognitively impaired) and 26 invalid performances. In total, 23 previously identified embedded PVTs derived from Verbal Fluency (VF), Trail Making Test (TMT), Stroop (SCWT), and Wisconsin Card Sorting Test (WCST) were examined. RESULTS:=.05-.22) with areas under the curve (AUCs) of.65-.81 and 19-54% sensitivity (≥89% specificity) at optimal cut-scores. When subdivided by impairment status, all PVTs except for WCST Failures to Maintain Set were significant (AUCs =.75-94) with 33-85% sensitivity (≥90% specificity) in the cognitively unimpaired group. Among the cognitively impaired group, most VF, TMT, and SCWT PVTs remained significant, albeit with decreased accuracy (AUCs =.65-.76) and sensitivities (19-54%) at optimal cut-scores, whereas all WCST PVTs were nonsignificant. Across groups, SCWT embedded PVTs evidenced the strongest psychometric properties. CONCLUSION:VF, TMT, and SCWT embedded PVTs generally demonstrated moderate accuracy for identifying invalid neuropsychological performance. However, performance on these non-memory-based PVTs from processing speed and executive functioning tests are not immune to the effects of cognitive impairment, such that alternate cut-scores (with reduced sensitivity if adequate specificity is maintained) are indicated in cases where the clinical history is consistent with cognitive impairment. In contrast, WCST indices generally had poor accuracy.