Multigene Panel Testing in a Large Cohort of Adults With Epilepsy

Background and ObjectivesAlthough genetic testing among children with epilepsy has demonstrated clinical utility and become a part of routine testing, studies in adults are limited. This study reports the diagnostic yield of genetic testing in adults with epilepsy.MethodsUnrelated individuals aged 18 years and older who underwent diagnostic genetic testing for epilepsy using a comprehensive, next-generation sequencing-based, targeted gene panel (range 89–189 genes) were included in this cross-sectional study. Clinical information, provided at the discretion of the ordering clinician, was reviewed and analyzed. Diagnostic yield was calculated for all individuals including by age at seizure onset and comorbidities based on clinician-reported information. The proportion of individuals with clinically actionable genetic findings, including instances when a specific treatment would be indicated or contraindicated due to a diagnostic finding, was calculated.ResultsAmong 2,008 individuals, a diagnostic finding was returned for 218 adults (10.9%), with clinically actionable findings in 55.5% of diagnoses. The highest diagnostic yield was in adults with seizure onset during infancy (29.6%, 0–1 year), followed by in early childhood (13.6%, 2–4 years), late childhood (7.0%, 5–10 years), adolescence (2.4%, 11–17 years), and adulthood (3.7%, ≥18 years). Comorbid intellectual disability (ID) or developmental delay resulted in a high diagnostic yield (16.0%), most notably for females (19.6% in females vs 12.3% in males). Among individuals with pharmacoresistant epilepsy, 13.5% had a diagnostic finding, and of these, 57.4% were clinically actionable genetic findings.DiscussionThese data reinforce the utility of genetic testing for adults with epilepsy, particularly for those with childhood-onset seizures, ID, and pharmacoresistance. This is an important consideration due to longer survival and the complexity of the transition from pediatric to adult care. In addition, more than half of diagnostic findings in this study were considered clinically actionable, suggesting that genetic testing could have a direct impact on clinical management and outcomes.

Tracheal lesion during shoulder surgery: a case report and systemic review of the literature

Pneumomediastinum (PNM) and pneumothorax (PNX) are documented complications of arthroscopic shoulder surgery (ATS). Plexus anesthetic block and tracheal lesions during endotracheal intubation are hypothesized to be the underlying risk factors; however, the actual evidence supporting this hypothesis is scarce.A case of bilateral laterocervical emphysema, subcutaneous edema, and signs of PNM after ATS performed under general anesthesia and supra-scapular nerve block is presented. An up-to-date systematic review of PNM/PNX during orthopedic surgery was performed, involving six databases: PubMed (1996–present), Embase (1974–present), Scopus (2004–present), SpringerLink (1950–present), Ovid Emcare (1995–present), and Google Scholar (2004–present).Twenty-five case studies met the eligibility criteria. In 24 cases, the patient underwent general anesthesia and orotracheal intubation; in 9 of these, a plexus anesthetic block was also performed. One case involved ATS under plexus anesthetic block only. In 10 cases, the diagnostic finding was PNM. In 5 cases, the diagnostic finding was associated with PNX. PNX was detected in 17 cases. In 2 cases, SE was found in the absence of any evidence of either PNM or PNX. A tracheal lesion was identified in 3 cases.Endotracheal intubation and loco-regional anesthesia are not the only predisposing risk factors at play in the pathogenesis of PNM/PNX. Rather, multi-factorial pathogenesis seems more probable, necessitating that specific attention is paid during ATS to the change in patient position on the operating bed, to any slipping of the endotracheal tube, to patient monitoring whilst under the drapes, and to the cuff pressure. PROSPERO registration number: CRD42021260370.

The Sonographic Appearance of Seminal Megavesicles, an Association With Autosomal Dominant Polycystic Kidney Disease: A Series Review

Megavesicles are an uncommon diagnostic finding during sonography of the bladder, especially when the examination is performed transabdominally. Although megavesicles are more likely seen with transrectal ultrasonography, computed tomogram (CT), vesiculography, or magnetic resonance imaging (MRI), it has been noted during transabdominal sonography for patients suffering from autosomal dominant polycystic kidney disease (ADPKD). When seminal vesicles become dilated, they are often visualized during transabdominal sonography. Two patient cases are provided of seminal megavesicles, associated with ADPKD and have documented sonographic findings. Both patient cases of megavesicles were discovered incidentally during the course of a renal sonogram. The importance of these diagnostic findings and the possible pathogenesis are provided.

Uniparental disomy in a population of 32,067 clinical exome trios

Purpose Data on the clinical prevalence and spectrum of uniparental disomy (UPD) remain limited. Trio exome sequencing (ES) presents a comprehensive method for detection of UPD alongside sequence and copy-number variant analysis. Methods We analyzed 32,067 ES trios referred for diagnostic testing to create a profile of UPD events and their disease associations. ES single-nucleotide polymorphism (SNP) and copy-number data were used to identify both whole-chromosome and segmental UPD and to categorize whole-chromosome results as isodisomy, heterodisomy, or mixed. Results Ninety-nine whole-chromosome and 13 segmental UPD events were identified. Of these, 29 were associated with an imprinting disorder, and 16 were associated with a positive test result through homozygous sequence variants. Isodisomy was more commonly observed in large chromosomes along with a higher rate of homozygous pathogenic variants, while heterodisomy was more frequent in chromosomes associated with imprinting or trisomy mosaicism (14, 15, 16, 20, 22). Conclusion Whole-chromosome UPD was observed in 0.31% of cases, resulting in a diagnostic finding in 0.14%. Only three UPD-positive cases had a diagnostic finding unrelated to the UPD. Thirteen UPD events were identified in cases with prior normal SNP chromosomal microarray results, demonstrating the additional diagnostic value of UPD detection by trio ES.

“Real world” use of a highly reliable imaging sign: “T2-FLAIR mismatch” for identification of IDH mutant astrocytomas

AbstractThe T2-FLAIR (fluid attenuated inversion recovery) mismatch sign is an easily detectable imaging sign on routine clinical MRI studies that suggests diagnosis of isocitrate dehydrogenase (IDH)–mutant 1p/19q non-codeleted gliomas. Multiple independent studies show that the T2-FLAIR mismatch sign has near-perfect specificity, but low sensitivity for diagnosing IDH-mutant astrocytomas. Thus, the T2-FLAIR mismatch sign represents a non-invasive radiogenomic diagnostic finding with potential clinical impact. Recently, false positive cases have been reported, many related to variable application of the sign’s imaging criteria and differences in image acquisition, as well as to differences in the included patient populations. Here we summarize the imaging criteria for the T2-FLAIR mismatch sign, review similarities and differences between the multiple validation studies, outline strategies to optimize its clinical use, and discuss potential opportunities to refine imaging criteria in order to maximize its impact in glioma diagnostics.

Pulmonary Coccidioidomycosis Mimicking Aspergillosis Fungus Ball

The genus Coccidioides is composed of C. immitis and C. posadasii. Both can cause coccidioidomycosis and are geographically restricted to certain areas of endemicity. The histopathologic features in pulmonary coccidioidomycosis include necrotizing granulomatous inflammation and the presence of spherules, which is considered to be a key diagnostic finding. Cavitary lung disease containing a fungal ball with branching septate hyphae is an unusual funding in pulmonary coccidioidomycosis but is typical for aspergillosis. We present a case of 42 year old man who underwent wedge resection of the lung for a persistent cavitary lesion. The microscopic examination shows a fungal ball composed of acute-angle branching septate hyphae, consistent with a diagnosis of aspergillosis. However, cultures and molecular testing by DNA sequencing of the 28S ribosomal DNA gene confirmed the identification of C. posadasii. This finding highlights the importance of exposure history and organism identification by either conventional cultivation or molecular testing in rendering an accurate diagnosis.

Progressive Supranuclear Palsy with Wall-Eyed Bilateral Internuclear Ophthalmoplegia Syndrome: Authors’ Second Case

Wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) syndrome has previously been reported in only 2 patients with progressive supranuclear palsy (PSP). Herein, we report a third case of WEBINO syndrome with PSP. The patient was an 81-year-old man who had experienced gradually increasing gait disturbance and occasional falls since the age of 78 years. At 80 years of age, he presented with cognitive impairment, parkinsonism, and oculomotor abnormalities. The oculomotor abnormalities consisted of vertical gaze palsy and loss of eye convergence. Brain magnetic resonance imaging demonstrated marked atrophy of the midbrain. He was diagnosed with PSP. At the age of 81 years, he presented with alternating extropia in his forward gaze and adduction paresis and outward nystagmus of the abducted eye in his horizontal gaze, both of which were compatible with WEBINO syndrome. Previously, we reported the first case of PSP with WEBINO syndrome, and another group recently reported a second case. In light of the previous cases and the present case, WEBINO syndrome in PSP should not be considered extremely rare. Furthermore, WEBINO syndrome has not been reported in other neurodegenerative disorders, which suggests that it might be a useful and specific diagnostic finding in PSP.