Surveillance for variant CJD: should more children with neurodegenerative diseases have autopsies?

OBJECTIVES: To report investigations performed in children with progressive neurodegenerative diseases reported to this UK study. DESIGN: Since 1997 paediatric surveillance for variant Creutzfeldt-Jakob disease (vCJD) has been performed by identifying children aged less than 16 years with progressive intellectual and neurological deterioration (PIND) and searching for vCJD among them. SETTING: The PIND Study obtains case details from paediatricians who notify via the British Paediatric Surveillance Unit. PARTICIPANTS: Between May 1997 and October 2017, a total of 2050 cases meeting PIND criteria had been notified and investigated. RESULTS: Six children had vCJD. 1819 children had other diagnoses, made in 12 cases by antemortem brain biopsy and in 15 by postmortem investigations. 225 children were undiagnosed: only 3 had antemortem brain biopsies and only 14 of the 108 who died were known to have had autopsies; postmortem neuropathological studies were carried out in just 10% (11/108) and only two had prion protein staining of brain tissue. Of the undiagnosed cases 43% were known to come from Asian British families. CONCLUSIONS: Most of the notified children had a diagnosis other than vCJD to explain their neurological deterioration. None of the undiagnosed cases had the clinical phenotype of vCJD but brain tissue was rarely studied to exclude vCJD. Clinical surveillance via the PIND Study remains the only practical means of searching for vCJD in UK children.

Investigation of the presence of HPV on KTP laser fibers following KTP laser treatment of papilloma.

OBJECTIVES: Recurrent respiratory papillomatosis is often treated with in-office laser procedures using a potassium titanyl phosphate (KTP) laser transmitted through a laser fiber. Although effective, this procedure has notable downsides, including the possibility of transmitting human papillomavirus (HPV) in the smoke plume and the high cost of these single-use fibers. The objective of this study is to determine if HPV can be detected on a laser fiber after use, with or without sterilization. METHODS: Twelve patients with laryngeal papillomas were treated with KTP laser energy transmitted via a KTP fiber. Ten fibers were sterilized in CIDEX (ASP, Irvine, California), a glutaraldehyde disinfectant, for 12 minutes, whereas two fibers were left unsterilized. Human papillomavirus DNA amplification was done on all 12 fiber samples with real-time polymerase chain reaction (PCR) using general primer mediated 5+ and 6+. Human papillomavirus genotyping detection was done using type specific probes and/or Sanger sequencing. RESULTS: Over 27 strains of HPV were not detected on KTP fibers after use, with or without sterilization. CONCLUSION: Human papillomavirus was undetectable by PCR on KTP laser fibers that were sterilized or unsterilized after use. Further studies are needed utilizing a transmission model to determine if HPV can be incubated from this fiber after sterilization. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:926-928, 2018.

Flexible Fiber-Optic High-Speed Imaging of Vocal Fold Vibration: A Preliminary Report.

OBJECTIVE: High-speed video (HSV) imaging of vocal fold vibration has been possible only through the rigid endoscope. This study reports that a fiberscope-based high-speed imaging system may allow HSV imaging of naturalistic voicing. MATERIALS AND METHODS: Twenty-two subjects were recorded using a commercially available black and white high-speed camera (Photron Motion Tools, 256 × 120 pixel, 2000 frames per second, 8 second acquisition time). The camera gain is set to +6 db. The camera is coupled to a standard fiber-optic laryngoscope (Olympus ENF P-4) with a 300-W Xenon light. Image acquisition was done by asking the subject to perform repeated phonation at modal phonation. Video images were processed using commercial video editing and video noise reduction software (After effects, Magix, and Neat Video 4.1). After video processing, the video images were analyzed using digital kymography (DKG). RESULTS: The HSV black and white video acquired by the camera is gray and lacks contrast. By adjustment of image contrast, brightness, and gamma and using noise reduction software, the flexible laryngoscopy image can be converted to video image files suitable for DKG and waveform analysis. The increased noise still makes edge tracking for objective analysis difficult, but subjective analysis of DKG plot is possible. CONCLUSIONS: This is the first report of HSV acquisition in an unsedated patient using a fiberscope. Image enhancement and noise reduction can enhance the HSV to allow extraction of the digital kymogram. Further image enhancement may allow for objective analysis of the vibratory waveform.

Serial in-office laser treatment of vocal fold leukoplakia: Disease control and voice outcomes.

OBJECTIVE: Although vocal fold (VF) leukoplakia is commonly treated with in-office laser, there is no data on its long-term effectiveness. This study hypothesizes that VF leukoplakia treated by serial in-office laser results in long-term disease control with maintenance of voice and minimal morbidity. STUDY DESIGN: Retrospective review (2008-2015). METHODS: Forty-six patients with VF leukoplakia treated by in-office KTP (potassium titanyl phosphate) or PDL (pulsed dye laser) were included. Median follow-up from final laser treatment was 19.6 months. Main outcomes included: 1) rate of disease control, 2) percentage of disease regression using ImageJ analysis. Secondary outcomes included vocal assessment using the Voice Handicap Index-10 (VHI-10). RESULTS: Patients underwent a median of 2 (range: 1-6) in-office laser treatments. Time between treatments was median 7.6 months. After final treatment, 19 patients (41.3%) had no disease; two patients (4.3%) progressed to invasive cancer; overall disease regression was median 77.1% (P < 0.001); and VHI-10 score decreased by median 5 (P = 0.037). Thirty-one patients (67.4%) were responders (controlled with in-office treatment only); failures were 13 patients (28.3%) who required operative intervention and two patients (4%) who underwent radiation. Compared to responders, failures demonstrated significantly shorter duration between treatments (median 2.3 vs. 8.9 months, P = 0.038) and significantly less regression (median 49.3% vs. 100%, P = 0.006). CONCLUSION: Serial outpatient KTP or PDL treatment of VF leukoplakia is effective for disease control with minimal morbidity and preservation of voice quality. We suggest that patients requiring repeated in-office treatment every 6 months may benefit from earlier operative intervention; other factors associated with in-office success remain unclear. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:1644-1651, 2017.

Volcanic Ash Activates the NLRP3 Inflammasome in Murine and Human Macrophages.

Volcanic ash is a heterogeneous mineral dust that is typically composed of a mixture of amorphous (glass) and crystalline (mineral) fragments. It commonly contains an abundance of the crystalline silica (SiO2) polymorph cristobalite. Inhalation of crystalline silica can induce inflammation by stimulating the NLRP3 inflammasome, a cytosolic receptor complex that plays a critical role in driving inflammatory immune responses. Ingested material results in the assembly of NLRP3, ASC, and caspase-1 with subsequent secretion of the interleukin-1 family cytokine IL-1ß. Previous toxicology work suggests that cristobalite-bearing volcanic ash is minimally reactive, calling into question the reactivity of volcanically derived crystalline silica, in general. In this study, we target the NLRP3 inflammasome as a crystalline silica responsive element to clarify volcanic cristobalite reactivity. We expose immortalized bone marrow-derived macrophages of genetically engineered mice and primary human peripheral blood mononuclear cells (PBMCs) to ash from the Soufrière Hills volcano as well as representative, pure-phase samples of its primary componentry (volcanic glass, feldspar, cristobalite) and measure NLRP3 inflammasome activation. We demonstrate that respirable Soufrière Hills volcanic ash induces the activation of caspase-1 with subsequent release of mature IL-1ß in a NLRP3 inflammasome-dependent manner. Macrophages deficient in NLRP3 inflammasome components are incapable of secreting IL-1ß in response to volcanic ash ingestion. Cellular uptake induces lysosomal destabilization involving cysteine proteases. Furthermore, the response involves activation of mitochondrial stress pathways leading to the generation of reactive oxygen species. Considering ash componentry, cristobalite is the most reactive pure-phase with other components inducing only low-level IL-1ß secretion. Inflammasome activation mediated by inhaled ash and its potential relevance in chronic pulmonary disease was further evidenced in PBMC using the NLRP3 small-molecule inhibitor CP-456,773 (CRID3, MCC950). Our data indicate the functional activation of the NLRP3 inflammasome by volcanic ash in murine and human macrophages in vitro. Cristobalite is identified as the apparent driver, thereby contesting previous assertions that chemical and structural imperfections may be sufficient to abrogate the reactivity of volcanically derived cristobalite. This is a novel mechanism for the stimulation of a pro-inflammatory response by volcanic particulate and provides new insight regarding chronic exposure to environmentally occurring particles.

Sinus thrombectomy for purulent cerebral venous sinus thrombosis utilizing a novel combination of the Trevo stent retriever and the Penumbra ACE aspiration catheter: the stent anchor with mobile aspiration technique.

Intracranial complications of sinusitis are rare but life threatening. We present a case of a 17-year-old woman with sinusitis who deteriorated over the course of 12 days from subdural empyema and global purulent cerebral venous sinus thrombosis. The patient was managed with surgery and mechanical thrombectomy utilizing a novel 'stent anchor with mobile aspiration technique', in which a Trevo stent retriever (Stryker) was anchored in the superior sagittal sinus (SSS) while a 5 MAX ACE reperfusion catheter (Penumbra) was passed back and forth from the SSS to the sigmoid sinus with resultant dramatic improvement in venous outflow. The patient was extubated on postoperative day 3 and was discharged with minimal lower extremity weakness on postoperative day 11. This is the first report using the Trevo stent retriever for sinus thrombosis. It is important to keep these rare complications in mind when evaluating patients with oral and facial infections.

Surgery for scoliosis in Duchenne muscular dystrophy.

BACKGROUND: Scoliosis in patients with Duchenne muscular dystrophy (DMD) is usually progressive and is treated with surgery. However, it is unclear whether the existing evidence is sufficiently scientifically rigorous to support a recommendation for spinal surgery for most patients with DMD and scoliosis. This is an updated review, and an updated search was undertaken in which no new studies were found for inclusion. OBJECTIVES: To determine the effectiveness and safety of spinal surgery in patients with DMD with scoliosis. We intended to test whether spinal surgery is effective in increasing survival and improving respiratory function, quality of life, and overall functioning, and whether spinal surgery is associated with severe adverse effects. SEARCH METHODS: On 16 June 2015 we searched the Cochrane Neuromuscular Disease Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and CINAHL Plus. We also searched ProQuest Dissertation and Thesis database (January 1980 to June 2015), the National Institutes of Health Clinical Trials Database (6 January 2015), and the WHO International Clinical Trials Registry Platform (17 June 2015), and checked references. We imposed no language restrictions. SELECTION CRITERIA: We planned to include controlled clinical trials using random or quasi-random allocation of treatment evaluating all forms of spinal surgery for scoliosis in patients with DMD in the review. The control interventions would have been no treatment, non-operative treatment, or a different form of spinal surgery. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. Two review authors independently examined the search results and evaluated the study characteristics against inclusion criteria in order to decide which studies to include in the review. MAIN RESULTS: Of the 49 relevant studies we found, none met the inclusion criteria for the review because they were not clinical trials, but prospective or retrospective reviews of case series. AUTHORS' CONCLUSIONS: Since no randomized controlled clinical trials were available to evaluate the effectiveness of scoliosis surgery in patients with DMD, we can make no good evidence-based conclusion to guide clinical practice. Patients with scoliosis should be informed as to the uncertainty of benefits and potential risks of surgery for scoliosis. Randomized controlled trials are needed to investigate the effectiveness of scoliosis surgery, in terms of quality of life, functional status, respiratory function, and life expectancy.

Sinus thrombectomy for purulent cerebral venous sinus thrombosis utilizing a novel combination of the Trevo stent retriever and the Penumbra ACE aspiration catheter: the stent anchor with mobile aspiration technique.

Intracranial complications of sinusitis are rare but life threatening. We present a case of a 17-year-old woman with sinusitis who deteriorated over the course of 12 days from subdural empyema and global purulent cerebral venous sinus thrombosis. The patient was managed with surgery and mechanical thrombectomy utilizing a novel 'stent anchor with mobile aspiration technique', in which a Trevo stent retriever (Stryker) was anchored in the superior sagittal sinus (SSS) while a 5 MAX ACE reperfusion catheter (Penumbra) was passed back and forth from the SSS to the sigmoid sinus with resultant dramatic improvement in venous outflow. The patient was extubated on postoperative day 3 and was discharged with minimal lower extremity weakness on postoperative day 11. This is the first report using the Trevo stent retriever for sinus thrombosis. It is important to keep these rare complications in mind when evaluating patients with oral and facial infections.

Modelling environmental factors correlated with podoconiosis: a geospatial study of non-filarial elephantiasis.

INTRODUCTION: The precise trigger of podoconiosis - endemic non-filarial elephantiasis of the lower legs - is unknown. Epidemiological and ecological studies have linked the disease with barefoot exposure to red clay soils of volcanic origin. Histopathology investigations have demonstrated that silicon, aluminium, magnesium and iron are present in the lower limb lymph node macrophages of both patients and non-patients living barefoot on these clays. We studied the spatial variation (variations across an area) in podoconiosis prevalence and the associated environmental factors with a goal to better understanding the pathogenesis of podoconiosis. METHODS: Fieldwork was conducted from June 2011 to February 2013 in 12 kebeles (administrative units) in northern Ethiopia. Geo-located prevalence data and soil samples were collected and analysed along with secondary geological, topographic, meteorological and elevation data. Soil data were analysed for chemical composition, mineralogy and particle size, and were interpolated to provide spatially continuous information. Exploratory, spatial, univariate and multivariate regression analyses of podoconiosis prevalence were conducted in relation to primary (soil) and secondary (elevation, precipitation, and geology) covariates. RESULTS: Podoconiosis distribution showed spatial correlation with variation in elevation and precipitation. Exploratory analysis identified that phyllosilicate minerals, particularly clay (smectite and kaolinite) and mica groups, quartz (crystalline silica), iron oxide, and zirconium were associated with podoconiosis prevalence. The final multivariate model showed that the quantities of smectite (RR = 2.76, 95% CI: 1.35, 5.73; p = 0.007), quartz (RR = 1.16, 95% CI: 1.06, 1.26; p = 0.001) and mica (RR = 1.09, 95% CI: 1.05, 1.13; p < 0.001) in the soil had positive associations with podoconiosis prevalence. CONCLUSIONS: More quantities of smectite, mica and quartz within the soil were associated with podoconiosis prevalence. Together with previous work indicating that these minerals may influence water absorption, potentiate infection and be toxic to human cells, the present findings suggest that these particles may play a role in the pathogenesis of podoconiosis and acute adenolymphangitis, a common cause of morbidity in podoconiosis patients.

Surgery for scoliosis in Duchenne muscular dystrophy.

BACKGROUND: Scoliosis in people with Duchenne muscular dystrophy is usually progressive and treated with surgery. However, it is unclear whether the existing evidence is sufficiently scientifically rigorous to support a recommendation for spinal surgery for most people with Duchenne muscular dystrophy and scoliosis. This is an updated review and an updated search was undertaken in which no new studies were found. OBJECTIVES: To determine the effectiveness and safety of spinal surgery in people with Duchenne muscular dystrophy with scoliosis. We intended to test whether spinal surgery is effective in increasing survival, improving respiratory function, improving quality of life and overall functioning; and whether spinal surgery is associated with severe adverse effects. SEARCH METHODS: We searched the specialized registers of the Cochrane Neuromuscular Disease Group (31 July 2012), MEDLINE (January 1966 to July 2012), EMBASE (January 1947 to July 2012), CENTRAL (2012, Issue 7 in the Cochrane Library), CINAHL Plus(January 1937 to July 2012), Proquest Dissertation and Thesis Database (January 1980 to July 2012), and the National Institute of Health Clinical Trials Database (July 2012). No language restrictions were imposed. SELECTION CRITERIA: We planned to include controlled clinical trials using random or quasi-random allocation of treatment evaluating all forms of spinal surgery for scoliosis in people with Duchenne muscular dystrophy in the review. The control interventions would have been no treatment, non-operative treatment, or a different form of spinal surgery. DATA COLLECTION AND ANALYSIS: Two authors independently examined the search results and evaluated the study characteristics against inclusion criteria to decide which ones would be included in the review. MAIN RESULTS: On searching, 47 studies were relevant but none met the inclusion criteria for the review, because they were not clinical trials but prospective or retrospective reviews of case series. AUTHORS' CONCLUSIONS: Since there were no randomized controlled clinical trials available to evaluate the effectiveness of scoliosis surgery in people with Duchenne muscular dystrophy, no evidence-based recommendation can be made for clinical practice. People with scoliosis should be informed about the uncertainty of benefits and potential risks of surgery for scoliosis. Randomized controlled trials are needed to investigate the effectiveness of scoliosis surgery, in terms of quality of life, functional status, respiratory function and life expectancy.

Acquired microcephaly: causes, patterns, motor and IQ effects, and associated growth changes.

OBJECTIVES: The goals were to identify and to classify causes and growth patterns of acquired (or progressive) microcephaly and to look for hypothesized correlations between causes, growth patterns, and developmental quotient/IQ. METHODS: Fifty-one children (24 boys), 0.7 to 11.3 years of age, with early occipitofrontal circumference measurements above and later ones below the second percentile (SD: -2.03) were studied through retrospective note and growth chart review, with formal assessments of developmental quotient or IQ (n = 34). RESULTS: Causes were classifiable into 5 groups as follows: idiopathic, familial, syndromic, symptomatic, and mixed. Four patterns of head growth were identified, as follows: type A, initial decrease from the normal range to below the second percentile, followed by growth below and parallel to the second percentile; type B, continued decrease away from the second percentile; type C, decrease below the normal range, with partial later recovery; type D, insufficient data. For 12 children, there were accompanying decreases in weight percentiles and for 5 of these in height percentiles as well. Infants with lower head circumference z scores at the end of the study also had lower z scores for final weight and final length. There was no correlation between causal group and growth pattern. Developmental quotient/IQ values were mostly <100 and did not correlate with head circumference z score, cause, or pattern. CONCLUSIONS: The classification of causal groups and growth patterns should aid clinical management. Neither cause nor pattern predicted outcomes. The associations with poor weight gain and body growth deserve further study.

Effect of cochlear implant technology in sequentially bilaterally implanted adults.

OBJECTIVE: Bilateral sequential cochlear implantation outcomes are dependent on many different factors. Newer technology in the second implanted ear may also contribute to outcome. This study examines the effect of cochlear implant technology on speech recognition outcomes in a population of adult patients who have undergone bilateral sequential implantation using different technologies in each ear. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary referral center. PATIENTS: Twenty adults who underwent bilateral sequential cochlear implantation with different technologies and processing strategies in each ear were patients for this study. Control Group A included patients (n = 8) who were simultaneously implanted, and Control Group B (n = 3) were patients who were sequentially implanted with the same technology. INTERVENTION: Bilateral sequential cochlear implantation. OUTCOME MEASURES: The outcome measure was the Consonant-Nucleus-Consonant monosyllabic word test administered in each implanted ear and in the binaural condition before and 1 year after operation. A multivariate analysis was performed to account for factors including duration of deafness, length of device usage, and severity of deafness. RESULTS: There was significant improvement from before to 1 year after the operation in word scores for the individual ears and in the binaural condition for all groups. All patients were consistent users of both devices, and the use of different technology in the second implanted ear did not affect the patients' ability to benefit from bilateral implantation despite the use of different devices and processing strategies. CONCLUSION: Bilateral sequential implantation with newer and/or differing technology in the second implanted ear did not reduce the benefits of bilateral stimulation and should not be considered a deterrent to second-sided implantation.

Conserved protective mechanisms in radiation and genetically attenuated uis3(-) and uis4(-) Plasmodium sporozoites.

Immunization with radiation attenuated Plasmodium sporozoites (RAS) elicits sterile protective immunity against sporozoite challenge in murine models and in humans. Similarly to RAS, the genetically attenuated sporozoites (GAPs) named uis3(-), uis4(-) and P36p(-) have arrested growth during the liver stage development, and generate a powerful protective immune response in mice. We compared the protective mechanisms in P. yoelii RAS, uis3(-) and uis4(-) in BALB/c mice. In RAS and GAPs, sterile immunity is only achieved after one or more booster injections. There were no differences in the immune responses to the circumsporozoite protein (CSP) generated by RAS and GAPs. To evaluate the role of non-CSP T-cell antigens we immunized antibody deficient, CSP-transgenic BALB/c mice, that are T cell tolerant to CSP, with P. yoelii RAS or with uis3(-) or uis4(-) GAPs, and challenged them with wild type sporozoites. In every instance the parasite liver stage burden was approximately 3 logs higher in antibody deficient CSP transgenic mice as compared to antibody deficient mice alone. We conclude that CSP is a powerful protective antigen in both RAS and GAPs viz., uis3(-) and uis4(-) and that the protective mechanisms are similar independently of the method of sporozoite attenuation.

Stroke in a child with neurofibromatosis type 2.

Neurofibromatosis types 1 (NF1) and 2 (NF2) are genetically distinct conditions caused by mutations in tumour suppressor genes that share a number of phenotypic features. Childhood stroke and vasculopathy have been associated with NF1, but not with NF2. We describe a case of brainstem stroke in a child with NF2.

Clinical and molecular phenotype of Aicardi-Goutieres syndrome.

Aicardi-Goutieres syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. AGS exhibits locus heterogeneity, with mutations identified in genes encoding the 3'-->5' exonuclease TREX1 and the three subunits of the RNASEH2 endonuclease complex. To define the molecular spectrum of AGS, we performed mutation screening in patients, from 127 pedigrees, with a clinical diagnosis of the disease. Biallelic mutations in TREX1, RNASEH2A, RNASEH2B, and RNASEH2C were observed in 31, 3, 47, and 18 families, respectively. In five families, we identified an RNASEH2A or RNASEH2B mutation on one allele only. In one child, the disease occurred because of a de novo heterozygous TREX1 mutation. In 22 families, no mutations were found. Null mutations were common in TREX1, although a specific missense mutation was observed frequently in patients from northern Europe. Almost all mutations in RNASEH2A, RNASEH2B, and RNASEH2C were missense. We identified an RNASEH2C founder mutation in 13 Pakistani families. We also collected clinical data from 123 mutation-positive patients. Two clinical presentations could be delineated: an early-onset neonatal form, highly reminiscent of congenital infection seen particularly with TREX1 mutations, and a later-onset presentation, sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurological function, most frequently due to RNASEH2B mutations. Mortality was correlated with genotype; 34.3% of patients with TREX1, RNASEH2A, and RNASEH2C mutations versus 8.0% RNASEH2B mutation-positive patients were known to have died (P=.001). Our analysis defines the phenotypic spectrum of AGS and suggests a coherent mutation-screening strategy in this heterogeneous disorder. Additionally, our data indicate that at least one further AGS-causing gene remains to be identified.

Congenital corectopia (eccentric pupils): a marker for chromosomal and central nervous system abnormality.

We present a case series of five children with congenital corectopia without any associated ocular cause: three had chromosomal abnormalities; one a probable prenatal diplegia, and one bilateral perisylvian dysplasia with vermian and midbrain hypoplasia. Bilateral congenital corectopia is an ophthalmic sign that merits chromosomal analysis and neuro-developmental assessment.