Faculty Bibliography

BACKGROUND:Extraneural metastasis of glioma is a rare event, often occurring in patients with advanced disease. Genomic alterations associated with extraneural glioma metastasis remain incompletely understood. METHODS:Ten patients at Memorial Sloan Kettering Cancer Center diagnosed with extraneural metastases of glioblastoma (9 patients) and gliosarcoma (1 patient) from 2003 to 2018 were included in our analysis. Patient characteristics, clinical course, and genomic alterations were evaluated. RESULTS:Patient age at diagnosis ranged from 14 to 73, with 7 men and 3 women in this group. The median overall survival from initial diagnosis and from diagnosis of extraneural metastasis was 19.6 months (range 11.2 to 57.5 months) and 5 months (range 1 to 16.1 months), respectively. The most common site of extraneural metastasis was bone, with other sites being lymph nodes, dura, liver, lung, and soft tissues. All patients received surgical resection and radiation, and 9 patients received temozolomide, with subsequent chemotherapy appropriate for individual cases. 1 patient had an Ommaya and then ventriculoperitoneal shunt placed, and 1 patient underwent craniectomy for cerebral edema associated with a brain abscess at the initial site of resection. Genomic analysis of primary tumors and metastatic sites revealed shared and private mutations with a preponderance of tumor suppressor gene alterations, illustrating clonal evolution in extraneural metastases. CONCLUSIONS:Several risk factors emerged for extraneural metastasis of glioblastoma and gliosarcoma, including sarcomatous dedifferentiation, disruption of normal anatomic barriers during surgical resection, and tumor suppressor gene alterations. Next steps with this work include validation of these genomic markers of glioblastoma metastases in larger patient populations and the development of preclinical models. This work will lead to a better understanding of the molecular mechanisms of metastasis to develop targeted treatments for these patients.

INTRODUCTION/BACKGROUND:According to evidence-based clinical practice guidelines, patients presenting with disabling stroke symptoms should be treated with intravenous tissue plasminogen activator (IV tPA) within 4.5 hours of time last known well. However, 25% of strokes are detected upon awakening ('wake-up strokes'; WUS) which renders patients ineligible for IV tPA administered via time-based treatment algorithms because it is impossible to establish a reliable time of symptom onset. We performed a systematic review and meta-analysis of the efficacy and safety of IV tPA compared with normal saline, placebo, or no treatment in patients with WUS using imaging-based treatment algorithms. METHODS:We searched Medline, Web of Science, and Scopus between January 1, 2006 and April 30, 2020. We included controlled trials (randomized or nonrandomized), observational cohort studies (prospective or retrospective), and single-arm studies in which adults with WUS were administered IV tPA after MR- or CT-based imaging. Our primary outcome was recovery at 90 days (defined as a modified Rankin Scale [mRS] score of 0-2) and our secondary outcomes were symptomatic intracranial hemorrhage (sICH) within 36 hours, mortality, and other adverse effects. RESULTS:We included 16 studies that enrolled a total of 14,017 patients. Most studies were conducted in Europe (37.5%) or North America (37.5%), and 1,757 patients (12.5%) received IV tPA. All studies used MRI-based (5 studies) or CT-based (10 studies) imaging selection and one study used a combination of modalities. Sixty-one percent of patients receiving IV tPA achieved mRS of 0-2 at 90 days (95% CI 51% to 70%; 12 studies), with a relative risk (RR) of 1.21 compared with patients not receiving IV tPA (95% CI 1.01 to 1.46; 4 studies). Three percent of patients receiving IV tPA experienced sICH within 36 hours (95% CI 2.5% to 4.1%; 16 studies), an RR of 4.00 compared with patients not receiving IV tPA (95% CI 2.85 to 5.61; 7 studies). CONCLUSIONS:This systematic review and meta-analysis suggests that IV tPA is associated with a better functional outcome at 90 days despite the increased but acceptable risk of sICH. Based on these results, IV tPA should be offered as a treatment for WUS patients with favorable neuroimaging findings.

OBJECTIVE:Recent studies on a rodent model of Parkinson's disease (PD) have raised the possibility of increased blood-brain barrier (BBB) permeability, demonstrated by histology, autoradiography, and positron emission tomography (PET). However, in human PD patients, in vivo evidence of increased BBB permeability is lacking. We examined the hypothesis that levodopa treatment increases BBB permeability in human subjects with PD, particularly in those with levodopa-induced dyskinesia (LID). METHODS:Rb concentration in brain tissue and blood, was estimated with good stability as a local measure of the volume of distribution. RESULTS:measured off- and on-levodopa infusion were also not significant for dyskinetic and non-dyskinetic subjects. CONCLUSION/CONCLUSIONS:Rb PET did not reveal significant changes in BBB permeability in PD patients.

Barrel subfields in rodent primary somatosensory cortex (SI) are important model systems for studying cortical organization and reorganization. During cortical reorganization that follows limb deafferentation, neurons in deafferented forelimb SI become responsive to previously unexpressed inputs from the lower jaw. Although the lower jaw barrel subfield (LJBSF) is a likely source of the input, this subfield has received little attention. Our aim was to describe the structural and functional organization of the normal LJBSF. To investigate LJBSF organization, a nomenclature for lower jaw skin surface was developed, cytochrome oxidase (CO) was used to label flattened-cut LJBSF sections, microelectrodes were used to map the lower jaw skin surface representation in SI, and electrolytic lesions, recovered from electrode penetrations, were used to align the physiological map to the underlying barrel map. LJBSF is a tear-shaped subfield containing approximately 24 barrels, arranged in eight mediolateral rows and a barrel-free zone capping the anterior border. The representation of the lower jaw skin consisting of chin vibrissae and microvibrissae embedded in common fur is somatotopically organized in a single map in the contralateral SI. This physiological map shows that the activity from the vibrissae aligns with the CO-staining of the underlying LJBSF. LJBSF barrels receive topographically ordered barrel-specific input from individual vibrissa and microvibrissae in the lower jaw but not from trident whiskers. The barrel-free zone receives topographically ordered input from the lower lip. These data demonstrating that the LJBSF is a highly organized subfield are essential for understanding its possible role in cortical reorganization.

INTRODUCTION/BACKGROUND:Levodopa/carbidopa intestinal gel (LCIG; carbidopa/levodopa enteral suspension) has been widely used and studied for the treatment of motor fluctuations in levodopa-responsive patients with advanced Parkinson's disease (PD) when other treatments have not given satisfactory results. Reduction in 'off'-time is a common primary endpoint in studies of LCIG, and it is important to assess the durability of this response. This systematic literature review was conducted to qualitatively summarise the data on the long-term effects of LCIG therapy on 'off'-time. METHODS:Studies were identified by searching PubMed, EMBASE and Ovid on 30 September 2019. Studies were included if they reported on patients with PD, had a sample size of ≥ 10, LCIG was an active intervention and 'off'-time was reported for ≥ 12 months after initiation of LCIG treatment. Randomised clinical trials, retrospective and prospective observational studies, and other interventional studies were included for selection. Data were collected on: 'off'-time (at pre-specified time periods and the end of follow-up), study characteristics, Unified Parkinson's Disease Rating Scale (UPDRS) II, III and IV total scores, dyskinesia duration, quality of life scores, non-motor symptoms and safety outcomes. RESULTS:Twenty-seven studies were included in this review. The improvement in 'off'-time observed shortly after initiating LCIG was maintained and was statistically significant at the end of follow-up in 24 of 27 studies. 'Off'-time was reduced from baseline to end of follow-up by 38-84% and was accompanied by a clinically meaningful improvement in quality of life. Stratified analysis of 'off'-time demonstrated mean relative reductions of 47-82% at 3-6 months and up to 83% reduction at 3-5 years of follow-up. Most studies reported significant improvements in activities of daily living and motor complications. Most frequent adverse events were related to the procedure or the device. CONCLUSION/CONCLUSIONS:In one of the largest qualitative syntheses of published LCIG studies, LCIG treatment was observed to provide a durable effect in reducing 'off'-time. INFOGRAPHIC/UNASSIGNED:Video Abstract.

Slowed information processing speed is among the earliest markers of cognitive impairment in multiple sclerosis (MS) and has been associated with white matter (WM) structural integrity. Localization of WM tracts associated with slowing, but not significant impairment, on specific cognitive tasks in pediatric and young age onset MS can facilitate early and effective therapeutic intervention. Diffusion tensor imaging data were collected on 25 MS patients and 24 controls who also underwent the Symbol Digit Modalities Test (SDMT) and the computer-based Cogstate simple and choice reaction time tests. Fractional anisotropy (FA), mean (MD), radial (RD) and axial (AD) diffusivities were correlated voxel-wise with processing speed measures. All DTI metrics of several white matter tracts were significantly different between groups (p < 0.05). Notably, higher MD, RD, and AD, but not FA, in the corpus callosum correlated with lower scores on both SDMT and simple reaction time. Additionally, all diffusivity metrics in the left corticospinal tract correlated negatively with SDMT scores, whereas only MD in the right superior fronto-occipital fasciculus correlated with simple reaction time. In conclusion, subtle slowing of processing speed is correlated with WM damage in the visual-motor processing pathways in patients with young age of MS onset.

Objective/UNASSIGNED:Evaluate whether the benefits of Mindfulness-Based Cognitive Therapy for Migraine (MBCT-M) on headache disability differs among people with episodic and chronic migraine (CM). Methods/UNASSIGNED:This is a planned secondary analysis of a randomized clinical trial. After a 30-day baseline, participants were stratified by episodic (6-14 d/mo) and CM (15-30 d/mo) and randomized to 8 weekly individual sessions of MBCT-M or wait list/treatment as usual (WL/TAU). Primary outcomes (Headache Disability Inventory; Severe Migraine Disability Assessment Scale [scores ≥ 21]) were assessed at months 0, 1, 2, and 4. Mixed models for repeated measures tested moderation with fixed effects of treatment, time, CM, and all interactions. Planned subgroup analyses evaluated treatment*time in episodic and CM. Results/UNASSIGNED:= 0.268). Conclusions/UNASSIGNED:MBCT-M is a promising treatment for reducing headache-related disability, with greater benefits in episodic than CM. Trial Registration Information/UNASSIGNED:ClinicalTrials.gov Identifier: NCT02443519. Classification of Evidence/UNASSIGNED:This study provides Class III evidence that MBCT-M reduces headache disability to a greater extent in people with episodic than CM.

Thorough assessment of performance validity has become an established standard of practice in neuropsychological assessment. While there has been a large focus on the development and cross-validation of embedded performance validity tests (PVTs) in recent years, new freestanding PVTs have also been developed, including the Word Choice Test (WCT) as part of the Advanced Clinical Solutions Effort System. And, while the WCT's general utility for identifying invalid performance has been demonstrated in the ensuing decade since its initial publication, optimal cut-scores and associated psychometric properties have varied widely across studies. This study sought to synthesize the existing diagnostic accuracy literature regarding the WCT via a systematic review and to conduct a meta-analysis to determine the performance validity cut-score that best maximizes sensitivity while maintaining acceptable specificity. A systematic search of the literature resulted in 14 studies for synthesis, with eight of those available for meta-analysis. Meta-analytic results revealed an optimal cut-score of ≤ 42 with 54% sensitivity and 93% specificity for identifying invalid neuropsychological test performance. Collectively, the WCT demonstrated adequate diagnostic accuracy as a PVT across a variety of populations. Recommendations for future studies are also provided.

Migraine is a prevalent primary headache disorder and is usually considered as benign. However, structural and functional changes in the brain of individuals with migraine have been reported. High frequency of white matter abnormalities, silent infarct-like lesions, and volumetric changes in both gray and white matter in individuals with migraine compared to controls have been demonstrated. Functional magnetic resonance imaging (MRI) studies found altered connectivity in both the interictal and ictal phase of migraine. MR spectroscopy and positron emission tomography studies suggest abnormal energy metabolism and mitochondrial dysfunction, as well as other metabolic changes in individuals with migraine. In this review, we provide a brief overview of neuroimaging studies that have helped us to characterize some of these changes and discuss their limitations, including small sample sizes and poorly defined control groups. A better understanding of alterations in the brains of patients with migraine could help not only in the diagnosis but may potentially lead to the optimization of a targeted anti-migraine therapy.

BACKGROUND AND PURPOSE/OBJECTIVE:Indirect consequences of the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) pandemic include those related to failure of patients to seek or receive timely medical attention for seemingly unrelated disease. We report our experience with stroke code imaging during the early pandemic months of 2020. MATERIALS AND METHODS/METHODS:Retrospective review of stroke codes during the 2020 pandemic and both 2020 and matched 2019 prepandemic months was performed. Patient variables were age, sex, hospital location, and severity of symptoms based on the NIHSS. We reviewed the results of CT of the head, CTA, CTP, and MR imaging examinations and classified a case as imaging-positive if any of the imaging studies yielded a result that related to the clinical indication for the study. Both year-to-year and sequential comparisons were performed between pandemic and prepandemic months. RESULTS:= .03). CONCLUSIONS:During our pandemic period, there was a significantly decreased number of stroke codes but simultaneous increases in positivity rates, symptom severity, and inpatient codes. We postulate that this finding reflects the documented reluctance of patients to seek medical care during the pandemic, with the shift toward a greater proportion of inpatient stroke codes potentially reflecting the neurologic complications of the virus itself.