Dysphagia Advances in Head and Neck Cancer.

Purpose of Review: This review summarises the current literature regarding head and neck cancer-associated dysphagia. Up-to-date evidence for dysphagia outcome measurement for this population is provided, in addition to recent innovations that aim to prevent, reduce or remediate the common and debilitating side effects of treatment. Recent Findings: Both patient-reported outcomes and clinical measures are necessary to capture the multi-dimensional nature of swallowing. A minimally important difference in scores has been calculated for some of these measures, to aid interpretation and powering of clinical trials. The number of dysphagia-related trials has increased, predominantly investigating optimal treatment for oropharyngeal HPV-positive disease, and speech and language pathology interventions using an impairment-based approach. Summary: Although substantial progress has been made, further work is necessary to establish a consensus over outcome measures. Modifying treatments may improve outcomes. Several trials are underway to establish the effectiveness of speech and language pathology dysphagia interventions.

Emergency Department Visits for Chronic Subdural Hematomas within 30 Days after Surgical Evacuation with and without Middle Meningeal Artery Embolization.

BACKGROUND AND PURPOSE: Middle meningeal artery embolization after surgical evacuation of a chronic subdural hematomas is associated with fewer treatment failures than surgical evacuation. We compared emergency department visits within 30 days for patients with chronic subdural hematomas with and without adjunctive middle meningeal artery embolization. MATERIALS AND METHODS: All cases of chronic subdural hematoma treated from January 1, 2018, through December 31, 2020, were retrospectively reviewed. Treatment was classified as surgery only or surgery combined with middle meningeal artery embolization. The primary outcome was 30-day emergency department presentation and readmission. RESULTS: Of 137 patients who met the study criteria, 28 (20%) underwent surgery combined with middle meningeal artery embolization. Of these 28 patients, 15 (54%) underwent planned middle meningeal artery embolization and 13 (46%) underwent embolization after surgical failure. The mean chronic subdural hematoma size at presentation in the group with surgery only (n = 109, 20.5 [SD, 6.9] mm) was comparable with that in the combined group (n = 28, 18.7 [SD, 4.5] mm; P = .16). A significantly higher percentage of the surgery-only group presented to the emergency department within 30 days compared with the combined group (32 of 109 [29%] versus 2 of 28 [7%] patients; P = .02). No significant difference was found with respect to readmission (16 [15%] versus 1 [4%] patient; P = .11). Nine patients (8%) in the surgery-only group were readmitted for significant reaccumulation or residual subdural hematoma compared with only 1 patient (4%) in the combined group (P = .40). CONCLUSIONS: Surgical evacuation combined with middle meningeal artery embolization in patients with chronic subdural hematoma is associated with fewer 30-day emergency department visits compared with surgery alone.

Arterioectatic Spinal Angiopathy of Childhood: Clinical, Imaging, Laboratory, Histologic, and Genetic Description of a Novel CNS Vascular Pathology.

Pediatric patients with myelopathy expressing intradural spinal vascular ectasia without arteriovenous shunting were studied at four tertiary referral neuropediatric centers. Patients were identified by retrospective review of institutional records and excluded if spinal vascular pathology could be classified into a previously described category of spinal vascular malformation. Four patients meeting the study criteria were enrolled in the study. Clinical, magnetic resonance imaging, catheter-directed angiography, laboratory, histological and genetic data were analyzed to characterize the disease process and elucidate underlying pathomechanisms. Our study revealed a highly lethal, progressive multi-segmental myelopathy associated with a unique form of non-inflammatory spinal angiopathy featuring diffuse enlargement and tortuosity of spinal cord arteries, spinal cord hyperemia, and spinal cord edema (Arterioectatic Spinal Angiopathy of Childhood). The condition was shown to mimic venous congestive myelopathy associated with pediatric spinal cord arteriovenous shunts on MRI but to have distinct pathognomonic findings on catheter-directed angiography. Clinicopathological, genetic, and neuroimaging features, which are described in detail, closely overlap with those of mitochondrial disease.

Utility of modified Rankin Scale for brain vascular malformations in hereditary hemorrhagic telangiectasia.

BACKGROUND: Approximately 10% of hereditary hemorrhagic telangiectasia (HHT) patients harbour brain vascular malformations (VMs). Intracranial hemorrhage (ICH) from brain VMs can lead to death or morbidity, while treatment options for brain VMs also have associated morbidity. The modified Rankin Scale (mRS) may provide an approach to identifying HHT-brain VM patients with poor outcomes, and their predictors. We aimed to measure the relationship between mRS score and brain VM, brain VM number, as well as other aspects of HHT, at enrollment and during prospective follow-up. METHODS: 1637 HHT patients (342 with brain VMs) were recruited from 14 HHT centres of the Brain Vascular Malformation Consortium since 2010 and followed prospectively (mean = 3.4 years). We tested whether the presence of brain VM, other HHT organ involvement, and HHT mutation genotype were associated with worse mRS scores at baseline and during follow-up, using linear mixed models, adjusting for age, sex, and year of visit. RESULTS: Presence of brain VMs was not associated with worse mRS score at baseline and there was no significant worsening of mRS with prospective follow-up in these patients; 92% had baseline mRS of 0-2. HHT-related gastrointestinal (GI) bleeding was associated with worse mRS scores at baseline (0.37, 95% CI 0.26-0.47, p < 0.001), as were history of anemia (0.35, 95% CI 0.27-0.43, p < 0.001) and liver VMs (0.19, 95% CI 0.09-0.30, p < 0.001). Presence of pulmonary arteriovenous malformations (AVMs) was not associated with worse mRS scores at baseline. mRS score was not associated with either HHT genotype (Endoglin vs ACVRL1). Only GI bleeding was associated with a significantly worsening mRS during prospective follow-up (0.64, 95% CI 0.21-1.08, p = 0.004). CONCLUSION: Most HHT-brain VM patients had good functional capacity (mRS scores 0-2) at baseline that did not change significantly over 3.4 mean years of follow-up, suggesting that mRS may not be useful for predicting or measuring outcomes in these patients. However, HHT patients with GI bleeding, anemia history or liver VMs had worse mRS scores, suggesting significant impact of these manifestations on functional capacity. Our study demonstrates the insensitivity of the mRS as an outcomes measure in HHT brain VM patients and reinforces the continued need to develop outcomes measures, and their predictors, in this group.

Predictors of mortality in patients with hereditary hemorrhagic telangiectasia.

BACKGROUND: Retrospective questionnaire and healthcare administrative data suggest reduced life expectancy in untreated hereditary hemorrhagic telangiectasia (HHT). Prospective data suggests similar mortality, to the general population, in Denmark's centre-treated HHT patients. However, clinical phenotypes vary widely in HHT, likely affecting mortality. We aimed to measure predictors of mortality among centre-treated HHT patients. HHT patients were recruited at 14 HHT centres of the Brain Vascular Malformation Consortium (BVMC) since 2010 and followed annually. Vital status, organ vascular malformations (VMs) and clinical symptoms data were collected at baseline and during follow-up (N = 1286). We tested whether organ VMs, HHT symptoms and HHT genes were associated with increased mortality using Cox regression analysis, adjusting for patient age, sex, and smoking status. RESULTS: 59 deaths occurred over average follow-up time of 3.4 years (max 8.6 years). A history of anemia was associated with increased mortality (HR = 2.93, 95% CI 1.37-6.26, p = 0.006), as were gastro-intestinal (GI) bleeding (HR = 2.63, 95% CI 1.46-4.74, p = 0.001), and symptomatic liver VMs (HR = 2.10, 95% CI 1.15-3.84, p = 0.015). Brain VMs and pulmonary arteriovenous malformations (AVMs) were not associated with mortality (p > 0.05). Patients with SMAD4 mutation had significantly higher mortality (HR = 18.36, 95% CI 5.60-60.20, p < 0.001) compared to patients with ACVRL1 or ENG mutation, but this estimate is imprecise given the rarity of SMAD4 patients (n = 33, 4 deaths). CONCLUSIONS: Chronic GI bleeding, anemia and symptomatic liver VMs are associated with increased mortality in HHT patients, independent of age, and in keeping with the limited treatment options for these aspects of HHT. Conversely, mortality does not appear to be associated with pulmonary AVMs or brain VMs, for which patients are routinely screened and treated preventatively at HHT Centres. This demonstrates the need for development of new therapies to treat chronic anemia, GI bleeding, and symptomatic liver VMs in order to reduce mortality among HHT patients.

Leveraging endogenous barley enzymes to turn lactose-containing dairy by-products into fermentable adjuncts for Saccharomyces cerevisiae-based ethanol fermentations.

Acid whey, a by-product of strained yogurt production, represents a disposal challenge for the dairy industry. Utilization schemes are currently limited; however, acid whey contains valuable components that could be used to create value-added products. One potential scheme would be the fermentation of acid whey into an alcoholic beverage. Sour beers are gaining popularity and acid whey, which is sour to begin with, could provide a new product opportunity. However, the main sugar of acid whey, lactose, cannot be fermented by the traditional brewer's yeast, Saccharomyces cerevisiae. It has been reported that barley contains enzymes capable of hydrolyzing lactose to glucose and galactose, which are fermentable by S. cerevisiae. We investigated whether a barley-based mash resulted in detectable hydrolysis of lactose into sugars fermentable by S. cerevisiae. We demonstrated the ability to hydrolyze lactose in acid whey using a barley-based mash, resulting in the average release of 3.70 g/L of glucose. Additionally, the subsequent liquid was fermented by S. cerevisiae to an average ethanol concentration of 3.23% alcohol by volume. This work demonstrates the ability to hydrolyze the lactose in acid whey using barley and the opportunity to use acid whey as a fermentable sugar source in beer production.

Apathy in rapid eye movement sleep behaviour disorder is common and under-recognized.

BACKGROUND AND PURPOSE: Apathy is an important neuropsychiatric feature of Parkinson's disease (PD), which often emerges before the onset of motor symptoms. Patients with rapid eye movement sleep behaviour disorder (RBD) have a high probability of developing PD in future. Neuropsychiatric problems are common in RBD, but apathy has not previously been detailed in this key prodromal population. METHODS: Eighty-eight patients with polysomnographically proven RBD, 65 patients with PD and 33 controls were assessed for apathy using the Lille Apathy Rating Scale. Cognition and depression were also quantified. The sensitivity of the Unified Parkinson's Disease Rating Scale screening questions for apathy and depression was calculated. RESULTS: A total of 46% of patients with RBD were apathetic, compared with 31% of patients with PD in our sample. Most patients with RBD with depression were apathetic but more than half of apathetic patients were not depressed. The sensitivity of the single Unified Parkinson's Disease Rating Scale screening question was only 33% for mild apathy and 50% for severe apathy. CONCLUSIONS: Apathy is common in RBD and is underestimated by a single self-report question. Recognition of apathy as a distinct neuropsychiatric feature in RBD could aid targeted treatment interventions and might contribute to the understanding of prodromal PD.

Pial Artery Supply as an Anatomic Risk Factor for Ischemic Stroke in the Treatment of Intracranial Dural Arteriovenous Fistulas.

BACKGROUND AND PURPOSE: Although intracranial dural arteriovenous fistulas are principally supplied by dural branches of the external carotid, internal carotid, and vertebral arteries, they can also be fed by pial arteries that supply the brain. We sought to determine the frequency of neurologic deficits following treatment of intracranial dural arteriovenous fistulas with and without pial artery supply. MATERIALS AND METHODS: One hundred twenty-two consecutive patients who underwent treatment for intracranial dural arteriovenous fistulas at our hospital from 2008 to 2015 were retrospectively reviewed. Patient data were examined for posttreatment neurologic deficits; patients with such deficits were evaluated for imaging evidence of cerebral infarction. Data were analyzed with multivariable logistic regression. RESULTS: Of 122 treated patients, 29 (23.8%) had dural arteriovenous fistulas with pial artery supply and 93 (76.2%) had dural arteriovenous fistulas without pial arterial supply. Of patients with pial artery supply, 4 (13.8%) had posttreatment neurologic deficits, compared with 2 patients (2.2%) without pial artery supply (P = .04). Imaging confirmed that 3 patients with pial artery supply (10.3%) had cerebral infarcts, compared with only 1 patient without pial artery supply (1.1%, P = .03). Increasing patient age was also positively associated with pial supply and treatment-related complications. CONCLUSIONS: Patients with dural arteriovenous fistulas supplied by the pial arteries were more likely to experience posttreatment complications, including ischemic strokes, than patients with no pial artery supply. The approach to dural arteriovenous fistula treatment should be made on a case-by-case basis so that the risk of complications can be minimized.

ToxEvaluator: an integrated computational platform to aid the interpretation of toxicology study-related findings.

Attempts are frequently made to investigate adverse findings from preclinical toxicology studies in order to better understand underlying toxicity mechanisms. These efforts often begin with limited information, including a description of the adverse finding, knowledge of the structure of the chemical associated with its cause and the intended pharmacological target. ToxEvaluator was developed jointly by Pfizer and the Comparative Toxicogenomics Database (http://ctdbase.org) team at North Carolina State University as an in silico platform to facilitate interpretation of toxicity findings in light of prior knowledge. Through the integration of a diverse set of in silico tools that leverage a number of public and proprietary databases, ToxEvaluator streamlines the process of aggregating and interrogating diverse sources of information. The user enters compound and target identifiers, and selects adverse event descriptors from a safety lexicon and mapped MeSH disease terms. ToxEvaluator provides a summary report with multiple distinct areas organized according to what target or structural aspects have been linked to the adverse finding, including primary pharmacology, structurally similar proprietary compounds, structurally similar public domain compounds, predicted secondary (i.e. off-target) pharmacology and known secondary pharmacology. Similar proprietary compounds and their associated in vivo toxicity findings are reported, along with a link to relevant supporting documents. For similar public domain compounds and interacting targets, ToxEvaluator integrates relationships curated in Comparative Toxicogenomics Database, returning all direct and inferred linkages between them. As an example of its utility, we demonstrate how ToxEvaluator rapidly identified direct (primary pharmacology) and indirect (secondary pharmacology) linkages between cerivastatin and myopathy.

Olfaction in Parkin single and compound heterozygotes in a cohort of young onset Parkinson's disease patients.

BACKGROUND: Parkin related Parkinson's disease (PD) is differentiated from idiopathic PD by absent or sparse Lewy bodies, and preserved olfaction. The significance of single Parkin mutations in the pathogenesis of PD is debated. OBJECTIVES: To assess olfaction results according to Parkin mutation status. To compare the prevalence of Parkin single heterozygous mutations in patients diagnosed with PD to the rate in healthy controls in order to establish whether these single mutations could be a risk factor for developing PD. METHODS: Parkin gene mutation testing was performed in young onset PD (diagnosed <50 years old) to identify three groups: Parkin homozygous or compound heterozygote mutation carriers, Parkin single heterozygote mutation carriers, and non-carriers of Parkin mutations. Olfaction was tested using the 40-item British version of the University of Pennsylvania smell identification test (UPSIT). RESULTS: Of 344 young onset PD cases tested, 8 (2.3%) were Parkin compound heterozygotes and 13 (3.8%) were Parkin single heterozygotes. Olfaction results were available in 282 cases (eight compound heterozygotes, nine single heterozygotes, and 265 non-carriers). In Parkin compound heterozygotes, the median UPSIT score was 33, interquartile range (IQR) 28.5-36.5, which was significantly better than in single Parkin heterozygotes (median 19, IQR 18-28) and non-carriers (median score 22, IQR 16-28) (ANOVA P < 0.001). These differences persisted after adjusting for age, disease duration, gender, and smoking (P < 0.001). There was no significant difference in UPSIT scores between single heterozygotes and non-carriers (P = 0.90). CONCLUSIONS: Patients with Parkin compound heterozygous mutations have relatively preserved olfaction compared to Parkin single heterozygotes and non-carriers. The prevalence of Parkin single heterozygosity is similar to the 3.7% rate reported in healthy controls.

Progressive versus Nonprogressive Intracranial Dural Arteriovenous Fistulas: Characteristics and Outcomes.

BACKGROUND AND PURPOSE: A minority of intracranial dural arteriovenous fistulas progress with time. We sought to determine features that predict progression and define outcomes of patients with progressive dural arteriovenous fistulas. MATERIALS AND METHODS: We performed a retrospective imaging and clinical record review of patients with intracranial dural arteriovenous fistula evaluated at our hospital. RESULTS: Of 579 patients with intracranial dural arteriovenous fistulas, 545 had 1 fistula (mean age, 45 ± 23 years) and 34 (5.9%) had enlarging, de novo, multiple, or recurrent fistulas (mean age, 53 ± 20 years; P = .11). Among these 34 patients, 19 had progressive dural arteriovenous fistulas with de novo fistulas or fistula enlargement with time (mean age, 36 ± 25 years; progressive group) and 15 had multiple or recurrent but nonprogressive fistulas (mean age, 57 ± 13 years; P = .0059, nonprogressive group). Whereas all 6 children had fistula progression, only 13/28 adults (P = .020) progressed. Angioarchitectural correlates to chronically elevated intracranial venous pressures, including venous sinus dilation (41% versus 7%, P = .045) and pseudophlebitic cortical venous pattern (P = .048), were more common in patients with progressive disease than in those without progression. Patients with progressive disease received more treatments than those without progression (median, 5 versus 3; P = .0068), but as a group, they did not demonstrate worse clinical outcomes (median mRS, 1 and 1; P = .39). However, 3 young patients died from intracranial venous hypertension and intracranial hemorrhage related to progression of their fistulas despite extensive endovascular, surgical, and radiosurgical treatments. CONCLUSIONS: Few patients with dural arteriovenous fistulas follow an aggressive, progressive clinical course despite treatment. Younger age at initial presentation and angioarchitectural correlates to venous hypertension may help identify these patients prospectively.

Inhibition of pathological brain angiogenesis through systemic delivery of AAV vector expressing soluble FLT1.

The soluble vascular endothelial growth factor (VEGF) receptor 1 (sFLT1) has been tested in both animals and humans for anti-angiogenic therapies, for example, age-related macular degeneration. We hypothesized that adeno-associated viral vector (AAV)-mediated sFLT1 expression could be used to inhibit abnormal brain angiogenesis. We tested the anti-angiogenic effect of sFLT1 and the feasibility of using AAV serotype 9 to deliver sFLT1 through intravenous injection (IV) to the brain angiogenic region. AAVs were packaged in AAV serotypes 1 and 2 (stereotactic injection) and 9 (IV injection). Brain angiogenesis was induced in adult mice through stereotactic injection of AAV1-VEGF. AAV2-sFLT02 containing sFLT1 VEGF-binding domain (domain 2) was injected into the brain angiogenic region, and AAV9-sFLT1 was injected into the jugular vein at the time of or 4 weeks after AAV1-VEGF injection. We showed that AAV2-sFLT02 inhibited brain angiogenesis at both time points. IV injection of AAV9-sFLT1 inhibited angiogenesis only when the vector was injected 4 weeks after angiogenic induction. Neither lymphocyte infiltration nor neuron loss was observed in AAV9-sFLT1-treated mice. Our data show that systemically delivered AAV9-sFLT1 inhibits angiogenesis in the mouse brain, which could be utilized to treat brain angiogenic diseases such as brain arteriovenous malformation.

Genetics of cerebral cavernous malformations: current status and future prospects.

Cerebral cavernous malformations (CCM) are vascular lesions which affect up to 0.5% of the general population, predisposing to headaches, seizures, cerebral hemorrhages and focal neurological deficits. CCM occurs in both sporadic and familial forms; familial cases follow an autosomal-dominant mode of inheritance and are caused by mutations in CCM1 (KRIT1), CCM2 (MGC4607), or CCM3 (PDCD10). Somatic mutations within the three CCM genes have been identified in CCM lesions from both sporadic and familial patients. We reviewed articles published in PubMed in English prior to March 2015 and provide an update on CCM mutations and the screening strategies used to identify them. Further, we summarize the specific clinical features related to CCM genotypes. As 5% to 15% of familial CCM cases remain genetically unexplained, we also discuss future approaches to expand understanding of the genetic architecture of CCM. Finally, we discuss possible genetic modifiers of CCM disease severity and progression. Understanding the genetic architecture of CCM is essential for an earlier diagnosis of the disease, predictive testing of at-risk patients, and design of targeted medical therapies of which there are currently none available.

Surgical treatment of cerebral cavernous malformations.

Cerebral cavernous malformations (CMs) are clusters of abnormally-formed, thin-walled blood vessels that tend to hemorrhage, resulting in focal neurological deficits, seizures, and even death, depending on the location of the lesion and extent of bleeding. Management of cerebral CMs can be reduced to the decision to observe or to surgically resect. The objective of the paper was to review options for surgical management of cerebral CMs. A university-based CM practice was examined for: 1) anatomical distribution of operatively managed CMs; and 2) surgical approaches to eloquent CMs. Although cerebral CMs can occur throughout the brain and can lead to significant neurological morbidity, even in highly eloquent locations, such as the brainstem, thalamus, and basal ganglia, experience demonstrates that the majority of CMs can be safely resected and that patients tend to experience long-term improvement in neurological function. The keys to good patient outcomes lie in appropriate patient selection and in thoughtful choice of a surgical approach that minimizes transgression of normal structures.

Association between Venous Angioarchitectural Features of Sporadic Brain Arteriovenous Malformations and Intracranial Hemorrhage.

BACKGROUND AND PURPOSE: Intracranial hemorrhage is the most serious outcome for brain arteriovenous malformations. This study examines associations between venous characteristics of these lesions and intracranial hemorrhage. MATERIALS AND METHODS: Statistical analysis was performed on a prospectively maintained data base of brain AVMs evaluated at an academic medical center. DSA, CT, and MR imaging studies were evaluated to classify lesion side, drainage pattern, venous stenosis, number of draining veins, venous ectasia, and venous reflux. Logistic regression analyses were performed to identify the association of these angiographic features with intracranial hemorrhage of any age at initial presentation. RESULTS: Exclusively deep drainage (OR, 3.42; 95% CI, 1.87-6.26; P < .001) and a single draining vein (OR, 1.98; 95% CI, 1.26-3.08; P = .002) were associated with hemorrhage, whereas venous ectasia (OR, 0.52; 95% CI, 0.34-0.78; P = .002) was inversely associated with hemorrhage. CONCLUSIONS: Analysis of venous characteristics of brain AVMs may help determine their prognosis and thereby identify lesions most appropriate for treatment.

Computational modeling of flow-altering surgeries in basilar aneurysms.

In cases where surgeons consider different interventional options for flow alterations in the setting of pathological basilar artery hemodynamics, a virtual model demonstrating the flow fields resulting from each of these options can assist in making clinical decisions. In this study, image-based computational fluid dynamics (CFD) models were used to simulate the flow in four basilar artery aneurysms in order to evaluate postoperative hemodynamics that would result from flow-altering interventions. Patient-specific geometries were constructed using MR angiography and velocimetry data. CFD simulations carried out for the preoperative flow conditions were compared to in vivo phase-contrast MRI measurements (4D Flow MRI) acquired prior to the interventions. The models were then modified according to the procedures considered for each patient. Numerical simulations of the flow and virtual contrast transport were carried out in each case in order to assess postoperative flow fields and estimate the likelihood of intra-aneurysmal thrombus deposition following the procedures. Postoperative imaging data, when available, were used to validate computational predictions. In two cases, where the aneurysms involved vital pontine perforator arteries branching from the basilar artery, idealized geometries of these vessels were incorporated into the CFD models. The effect of interventions on the flow through the perforators was evaluated by simulating the transport of contrast in these vessels. The computational results were in close agreement with the MR imaging data. In some cases, CFD simulations could help determine which of the surgical options was likely to reduce the flow into the aneurysm while preserving the flow through the basilar trunk. The study demonstrated that image-based computational modeling can provide guidance to clinicians by indicating possible outcome complications and indicating expected success potential for ameliorating pathological aneurysmal flow, prior to a procedure.

Kikuchi-Fujimoto Disease: part of the differential diagnosis of cervical lymphadenopathy in an HIV-positive patient.

A 38-year-old HIV-positive Nigerian woman presented with a three-week history of cervical lymphadenopathy, night sweats, weight loss and fever. Provisional diagnoses of tuberculosis and lymphoma were considered; however, a histological diagnosis of Kikuchi-Fujimoto Disease was reached. This rare benign disease has presenting features that mimic more serious conditions commonly occurring in HIV-positive patients. This case report emphasises the importance of Kikuchi-Fujimoto Disease in the differential diagnosis of cervical lymphadenopathy in HIV-positive patients.