Faculty Bibliography

OBJECTIVE:To report a case of petrous apicitis that manifested as chronic migraine without aura and to discuss the pathophysiological mechanisms behind this presentation. BACKGROUND:Petrous apicitis is a rare complication of acute otitis media with varied clinical presentations that stem from the close proximity of the petrous apex to numerous neurovascular structures. Headache is among the common symptoms of petrous apicitis. METHODS:A case of new onset headache in the setting of petrous apicitis with symptomatic response to antibiotic therapy was reported. We provided a brief review of peripheral pathophysiological mechanisms of migraine and correlated to mechanism of headache in petrous apicitis. RESULTS:A 65-year-old man with chronic otitis externa/media presented with ongoing headache fulfilling International Classification of Headache Disorders 3rd edition (ICHD-3) criteria for chronic migraine without aura that persisted despite undergoing right mastoidectomy and tympanoplasty with multiple courses of oral antibiotic therapy for his chronic otitis. MRI brain revealed petrous apicitis, otomastoiditis, and clival osteomyelitis. His imaging findings improved and his migraine-like headache completely resolved after treatment with a prolonged course of antibiotics. CONCLUSIONS:Petrous apicitis can present as a headache with features of migraine, and in this case in particular, as chronic migraine without aura. The pathophysiological mechanisms that may underlie the generation of migraine-like headache in petrous apicitis may include the activation of nociceptive fibers within the periosteum of the petrous apex and clivus whose cell bodies originate in the trigeminal ganglion and upper cervical dorsal root ganglia. By treating the peripheral pathology, resolution of the headache may be achieved.

OBJECTIVES/OBJECTIVE:The objective of this study was to compare safety and efficacy of patent foramen ovale (PFO) closure compared with medical therapy in patients with cryptogenic stroke (CS). BACKGROUND:The role of PFO closure in preventing recurrent stroke in patients with prior CS has been controversial. METHODS:We searched PubMed, EMBASE, the Cochrane Central Register of Controlled trials, and the clinical trial registry maintained at clinicaltrials.gov for randomized control trials that compared device closure with medical management and reported on subsequent stroke and adverse events. Event rates were compared using a forest plot of relative risk using a random-effects model assuming interstudy heterogeneity. RESULTS: = 27%, P = 0.002). The presence/absence of atrial septal aneurysm (P = 0.52) had no effect on the outcome. CONCLUSION/CONCLUSIONS:PFO closure is associated with a significant reduction in the risk of stroke compared to medical management. However, it causes an increased risk of atrial fibrillation.

BACKGROUND:We aim to describe and psychometrically validate the Rett Syndrome Motor Evaluation Scale, a 25-item ordinal scale examining (loco-)motor function across six sections: standing, sitting, transitions, walking, running, and walking up or downstairs. METHODS:We illustrate the process of item construction and validation, report findings and normative data obtained on a standardization sample of 60 patients with Rett syndrome. We investigate the validity and reliability of the scale and illustrate its psychometric properties using modern multivariate techniques of data analysis. RESULTS:Sixty patients with Rett syndrome were included (all female; mean age 12.45 (S.D. 8.75) years). The multidimensional latent structure of the scale was supported by the results of the confirmatory factor analysis. Rett Syndrome Motor Evaluation Scale showed strong internal consistency reliability as well as excellent inter-rater agreement. The Rett Syndrome Motor Evaluation Scale scores were not predicted by age, but were associated with disease severity, degree of spasticity, and hand dysfunction. We also identified three latent classes with different degrees of impairment. CONCLUSIONS:Rett Syndrome Motor Evaluation Scale is a new, valid, and reliable scale that can be introduced in clinical practice when assessing (loco-)motor function in Rett syndrome.

BACKGROUND:Recent studies estimate nearly half of the US population can access mobile medical applications (apps) on their smartphones. The are no systematic data available on apps focused on stroke survivors/caregivers. OBJECTIVE:To identify apps (a) designed for stroke survivors/caregivers, (b) dealing with a modifiable stroke risk factor (SRF), or (c) were developed for other purposes but could potentially be used by stroke survivors/caregivers. METHODS:A systematic review of the medical apps in the US Apple iTunes store was conducted between August 2013 and January 2016 using 18 predefined inclusion/exclusion criteria. SRFs considered were: diabetes, hypertension, smoking, obesity, atrial fibrillation, and dyslipidemia. RESULTS:Out of 30,132 medical apps available, 843 (2.7%) eligible apps were identified. Of these apps, (n = 74, 8.7%) apps were specifically designed for stroke survivors/caregivers use and provided the following services: language/speech therapy (n = 28, 37%), communication with aphasic patients (n = 19, 25%), stroke risk calculation (n = 11, 14%), assistance in spotting an acute stroke (n = 8, 10%), detection of atrial fibrillation (n = 3, 4%), direction to nearby emergency room (n = 3, 4%), physical rehabilitation (n = 3, 4%), direction to the nearest certified stroke center (n = 1, < 2%), and visual attention therapy (n = 1, <2%). 769 apps identified that were developed for purposes other than stroke. Of these, the majority (n = 526, 68%) addressed SRFs. CONCLUSIONS:Over 70 medical apps exist to specifically support stroke survivors/caregivers and primarily targeted language and communication difficulties. Apps encompassing most stroke survivor/caregiver needs could be developed and tested to ensure the issues faced by these populations are being adequately addressed.

BACKGROUND: There is no effective therapy for patients (pts) with IDH-mutant gliomas that progress after RT and chemotherapy. At time of progression, these tumors have often transformed to glioblastoma (GBM) and have increased numbers of somatic mutations, i.e. have a ?hypermutator phenotype?. We hypothesized that there is synergistic efficacy of Avelumab (anti-PD-L1) combined with HFRT in pts with secondarily trans- formed IDH-mutant GBMs. Safety-lead-in results will be presented.
METHOD(S): This is a phase II, open-label, single-arm, multicenter study of Avelumab with HFRT in adults with transformed IDH-mutant GBM who previously received RT and TMZ and/or PCV. All pts received Avelumab 10 mg/kg IV followed at Day 8 by HFRT (25 Gy in 5 daily 5-Gy fractions) and then Avelumab 10 mg/kg IV every 2 weeks. A 3 + 3 design was used for a 6-patient safety-lead-in cohort. Adverse events were recorded according to CTCAE.
RESULT(S): Six pts (F=4, M=2) with a median age= 45.5 yrs (range 31.5-54.4 yrs) were enrolled in the safety-lead-in cohort. No DLT was observed. Grade >= 3 AEs included increased cerebral edema (3 pts), hyponatremia (1 pt) and worsening hemiparesis (3 pts). Grade <= 2 AEs included nausea, hypothyroidism, lymphopenia, thrombocytopenia, transaminase elevation, and fever/chills. Median follow-up time was 8.9 mo. Best treatment response was SD in 1 patient. At time of last follow-up all pts have discontinued treatment for PD. Median PFS was 4.2 mo (range 1.4-5.7). Median OS was 10.1 (range 6.8-21+) mo. 4 pts (67%) died, 2 pts remain alive in follow-up at 6.9 and 21.6 months after treatment initiation. The study was closed after the safety lead-in completed enrollment due to slow accrual.
CONCLUSION(S): Avelumab combined with HFRT was tolerable without dose-limiting toxicity in this safety-lead-in cohort of adult patients with transformed IDH-mutant GBM. Further studies are necessary to determine efficacy of this treatment regimen

OBJECTIVE:To determine the underlying etiology in a patient with progressive dementia with extrapyramidal signs and chronic inflammation referred to the National Institutes of Health Undiagnosed Diseases Program. METHODS:Extensive investigations included metabolic profile, autoantibody panel, infectious etiologies, genetic screening, whole exome sequencing and the phage-display assay, VirScan, for viral immune responses. An etiological diagnosis was established post-mortem. RESULTS:Using VirScan, enrichment of dengue viral antibodies were detected in cerebrospinal fluid as compared to serum. No virus was detected in serum or cerebrospinal fluid, but post-mortem analysis confirmed dengue virus in the brain by immunohistochemistry, in situ hybridization, quantitative polymerase chain reaction and sequencing. Dengue virus was also detectable by polymerase chain reaction and sequencing from brain biopsy tissue collected 33 months ante-mortem, confirming a chronic infection despite a robust immune response directed against the virus. Immunoprofiling and whole exome sequencing of the patient did not reveal any immunodeficiency and sequencing of the virus demonstrated wild-type dengue virus in the central nervous system. INTERPRETATION/CONCLUSIONS:Dengue virus is the most common arbovirus worldwide and represents a significant public health concern. Infections with dengue virus are usually self-limiting and chronic dengue infections have not been previously reported. Our findings suggest that dengue virus infections may persist in the central nervous system and should be considered in patients with progressive dementia with extrapyramidal features in endemic regions or with relevant travel history. Further, this work highlights the utility of comprehensive antibody profiling assays to aid in the diagnosis of encephalitis of unknown etiologies. This article is protected by copyright. All rights reserved.

The glossopharyngeal and vagus cranial nerves provide the brainstem with sensory inputs from different receptors in the heart, lung, and vasculature. This afferent information is critical for the short-term regulation of arterial blood pressure and the buffering of emotional and physical stressors. Glossopharyngeal afferents supply the medulla with continuous mechanoreceptive signals from baroreceptors at the carotid sinus. Vagal afferents ascending from the heart supply mechanoreceptive signals from baroreceptors in different reflexogenic areas including the aortic arch, atria, ventricles, and pulmonary arteries. Ultimately, afferent information from each of these distinct pressure/volume baroreceptors is all relayed to the nucleus tractus solitarius, integrated within the medulla, and used to rapidly adjust sympathetic and parasympathetic activity back to the periphery. Lesions that selectively destroy the afferent fibers of the vagus and/or glossopharyngeal nerves can interrupt the transmission of baroreceptor signaling, leading to extreme blood pressure fluctuations. Vagal efferent neurons project back to the heart to provide parasympathetic cholinergic inputs. When activated, they trigger profound bradycardia, reduce myocardial oxygen demands, and inhibit acute inflammation. Impairment of the efferent vagal fibers seems to play a role in stress-induced neurogenic heart disease (i.e., takotsubo cardiomyopathy). This focused review describes: (1) the importance of the vagus and glossopharyngeal afferent neurons in regulating arterial blood pressure and heart rate, (2) how best to assess afferent and efferent cardiac vagal function in the laboratory, and (3) two clinical phenotypes that arise when the vagal and/or glossopharyngeal nerves do not survive development or are functionally impaired.

OBJECTIVE:Review the effect of orthostatic hypotension (OH) and rapid-eye-movement sleep behavioural disorder (RBD) on survival, cognitive impairment and postural stability, and discuss pathogenic mechanisms involved in the association of these two common non-motor features with relevant clinical outcomes in α-synucleinopathies. METHODS:We searched PubMed (January 2007-February 2019) for human studies of OH and RBD evaluating cognitive impairment, postural instability, and survival in Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA) and pure autonomic failure (PAF). Included studies were analysed for design, key results and limitations as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS:OH and RBD showed a positive association with cognitive impairment in PD and DLB, conflicting association in PAF, and no association in MSA. OH was correlated with incident falls and postural instability in PD and DLB but not in MSA. The association between RBD and postural instability was inconclusive; positive in five studies, negative in seven. OH, but not RBD, correlated with reduced survival in PD, DLB and MSA. The combination of OH and RBD was associated with cognitive impairment and more rapid progression of postural instability. CONCLUSIONS:OH and RBD yielded individual and combined negative effects on disability in α-synucleinopathies, reflecting a 'malignant' phenotype of PD with early cognitive impairment and postural instability. Underlying mechanisms may include involvement of selected brainstem cholinergic and noradrenergic nuclei.

ONC201, the first bitopic DRD2 antagonist for clinical oncology, has shown efficacy in H3 K27M-mutant glioma. We performed an integrated preclinical and clinical analysis of ONC201 in thalamic H3 K27Mmutant glioma. ONC201 was effective in mouse intra-uterine electroporation (IUE)-generated H3 K27M-mutant gliomas, with an in vitro IC50 of 500 nM and 50% prolongation of median survival in vivo (p=0.02, n=14). Elevated DRD2 expression was found in the thalamus of non-malignant brain tissue, leading to the hypothesis that thalamic tumors may be a particularly ONC201-sensitive sub-group. We analyzed thalamic H3 K27Mmutant glioma patients treated with ONC201 as of the 05/22/2019 cutoff date, which included patients who had recurrent disease prior to initiating ONC201 (n=20; 15-73 years old) and post-radiation non-recurrent patients (n=11; 5-19 years old). As of 5/22/2019, 10 of 20 recurrent patients and 9 of 11 non-recurrent patients remain on-treatment. Median PFS has not been reached for either cohort: median follow-up of 2.2 months (range: 0.6-37.9) for recurrent patients and 10.6 months (range: 4.3-20.5) from diagnosis for non-recurrent patients. Best response so far by RANO includes 1 CR, 2 PR, 7 SD, 9 PD, 1 NE for recurrent patients and 1 PR, 7 SD, 3 PD for non-recurrent patients. Additionally, 3 recurrent (-66%, -47%, -34%) and 2 non-recurrent (-40%, -10%) patients experienced regressions but are not yet confirmed PRs. For recurrent patients, median onset of response is 3.5 months (range: 2.2-3.8) and median duration of response has not been reached with a median follow-up of 12.5 months (range: 8.1-32.8). Preliminary analyses demonstrated a strong correlation of cell-free tumor DNA in plasma and CSF with MRI response. In summary, ONC201 demonstrates promising clinical efficacy in thalamic H3 K27M-mutant glioma patients, regardless of age. Micro-environmental DRD2 expression may enhance the overall ONC201 response and extend its therapeutic utility beyond H3 K27M-mutant glioma