Diagnostic accuracy of frozen section in Central nervous system lesions, a 10-year study.

How to Cite This Article: Khoddami M, Akbarzadeh A, Mordai A, Bidari Zerehpoush F, Alipour H, Samadzadeh S, Alipour B.Diagnostic Accuracy of Frozen Section of Central Nervous System Lesions: A 10-Year Study. Iran J Child Neurol. 2015 Winter;9(1):25-30. AbstractObjectiveDefinitive diagnosis of the central nervous system (CNS) lesions is unknown prior to histopathological examination. To determine the method and the endpoint for surgery, intraoperative evaluation of the lesion helps the surgeon.In this study, the diagnostic accuracy and pitfalls of using frozen section (FS) ofCNS lesions is determined.Materials & MethodsIn this retrospective study, we analyzed the results of FS and permanent diagnoses of all CNS lesions by reviewing reports from 3 general hospitals between March 2001 and March 2011.Results273 cases were reviewed and patients with an age range from 3 to 77 years of age were considered. 166 (60.4%) had complete concordance between FS and permanent section diagnosis, 83 (30.2%) had partial concordance, and 24 cases (9.5%) were discordant. Considering the concordant and partially concordant cases, the accuracy rate was 99.5%, sensitivity was 91.4%, specificity was 99.7%, and positive and negative predictive values were 88.4% and 99.8%, respectively.ConclusionOur results show high sensitivity and specificity of FS diagnosis in the evaluation of CNS lesions. A Kappa agreement score of 0.88 shows high concordance for FS results with permanent section. Pathologist’s misinterpretation, small biopsy samples (not representative of the entire tumor), suboptimal slides, and inadequate information about tumor location and radiologic findings appear to be the major causes for these discrepancies indicated from our study. ReferencesTaxy JB, Anthony G. Biopsy interpretation: the frozen section. 1st ed. China: Lippincott Williams & Wilkins; 2010. P.301-3.Somerset HL, Kleinschmidt-DeMasters BK. Approach to the intraoperative consultation for neurosurgical specimens. Adv Anat Pathol 2011; 18:446-9. doi: 10.1097/ PAP.0b013e3182169934.Regragui A, Amarti Riffi A, Maher M, El Khamlichi A, Saidi A. Accuracy of Intraoperative diagnosis in central nervous system tumors: report of 1315 cases. Neurochirurgie 2003; 49(2-3 Pt 1):67-72.Plesec TP, Prayson RA. Frozen section discrepancy in the evaluation of central nervous system tumors. Arch Pathol Lab Med 2007; 131:1532-40.Savargaonkar P, Farmer PM. Utility of intra-operative consultations for the diagnosis of central nervous system lesions. Ann Clin Lab Sci 2001; 31:133-9.Talan-Hraniloviæ J, Vuèiæ M, Ulamec M, Belicza M. Intraoperative frozen section analysis in of the central nervous system and pituitary gland pathology. Acta Clin Croat 2005; 44:217-21.Roessler K, Dietrich W, Kitz K. High diagnostic accuracy of cytologic smears of central nervous system tumors. A 15-year experience based on 4,172 patients. Acta Cytol 2002; 46:667-74.Ud Din N, Memon A, Idress R, Ahmad Z, Hasan S. Central Nervous System Lesions: Correlation of  Intraoperative and Final Diagnoses, Six Year Experience at a Referral Centre in a Developing Country, Pakistan. Asian Pac J Cancer Prev 2011; 12:1435-7.Burger PC, Scheithauer BW. Tumors of the Central Nervous System. In: AFIP Atlas of Tumor Pathology Series 4. Washington DC: American Registry of Pathology; 2007.Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, et al. The 2007 WHO Classification of Tumours of the Central Nervous System. Acta Neuropathol. 2007; 114: 97–109. doi: 10.1007/s00401- 007-0243-

The Acute Optic Neuritis Network (ACON): Study protocol of a non-interventional prospective multicenter study on diagnosis and treatment of acute optic neuritis

Optic neuritis (ON) often occurs at the presentation of multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD). The recommended treatment of high-dose corticosteroids for ON is based on a North American study population, which did not address treatment timing or antibody serostatus. The Acute Optic Neuritis Network (ACON) presents a global, prospective, observational study protocol primarily designed to investigate the effect of time to high-dose corticosteroid treatment on 6-month visual outcomes in ON. Patients presenting within 30 days of the inaugural ON will be enrolled. For the primary analysis, patients will subsequently be assigned into the MS-ON group, the aquapotin-4-IgG positive ON (AQP4-IgG+ON) group or the MOG-IgG positive ON (MOG-IgG+ON) group and then further sub-stratified according to the number of days from the onset of visual loss to high-dose corticosteroids (days-to-Rx). The primary outcome measure will be high-contrast best-corrected visual acuity (HC-BCVA) at 6 months. In addition, multimodal data will be collected in subjects with any ON (CIS-ON, MS-ON, AQP4-IgG+ON or MOG-IgG+ON, and seronegative non-MS-ON), excluding infectious and granulomatous ON. Secondary outcomes include low-contrast best-corrected visual acuity (LC-BCVA), optical coherence tomography (OCT), magnetic resonance imaging (MRI) measurements, serum and cerebrospinal fluid (CSF) biomarkers (AQP4-IgG and MOG-IgG levels, neurofilament, and glial fibrillary protein), and patient reported outcome measures (headache, visual function in daily routine, depression, and quality of life questionnaires) at presentation at 6-month and 12-month follow-up visits. Data will be collected from 28 academic hospitals from Africa, Asia, the Middle East, Europe, North America, South America, and Australia. Planned recruitment consists of 100 MS-ON, 50 AQP4-IgG+ON, and 50 MOG-IgG+ON. This prospective, multimodal data collection will assess the potential value of early high-dose corticosteroid treatment, investigate the interrelations between functional impairments and structural changes, and evaluate the diagnostic yield of laboratory biomarkers. This analysis has the ability to substantially improve treatment strategies and the accuracy of diagnostic stratification in acute demyelinating ON. Trial registration: ClinicalTrials.gov, identifier: NCT05605951

The Acute Optic Neuritis Network (ACON): Study protocol of a non-interventional prospective multicenter study on diagnosis and treatment of acute optic neuritis

Optic neuritis (ON) often occurs at the presentation of multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD). The recommended treatment of high-dose corticosteroids for ON is based on a North American study population, which did not address treatment timing or antibody serostatus. The Acute Optic Neuritis Network (ACON) presents a global, prospective, observational study protocol primarily designed to investigate the effect of time to high-dose corticosteroid treatment on 6-month visual outcomes in ON. Patients presenting within 30 days of the inaugural ON will be enrolled. For the primary analysis, patients will subsequently be assigned into the MS-ON group, the aquapotin-4-IgG positive ON (AQP4-IgG+ON) group or the MOG-IgG positive ON (MOG-IgG+ON) group and then further sub-stratified according to the number of days from the onset of visual loss to high-dose corticosteroids (days-to-Rx). The primary outcome measure will be high-contrast best-corrected visual acuity (HC-BCVA) at 6 months. In addition, multimodal data will be collected in subjects with any ON (CIS-ON, MS-ON, AQP4-IgG+ON or MOG-IgG+ON, and seronegative non-MS-ON), excluding infectious and granulomatous ON. Secondary outcomes include low-contrast best-corrected visual acuity (LC-BCVA), optical coherence tomography (OCT), magnetic resonance imaging (MRI) measurements, serum and cerebrospinal fluid (CSF) biomarkers (AQP4-IgG and MOG-IgG levels, neurofilament, and glial fibrillary protein), and patient reported outcome measures (headache, visual function in daily routine, depression, and quality of life questionnaires) at presentation at 6-month and 12-month follow-up visits. Data will be collected from 28 academic hospitals from Africa, Asia, the Middle East, Europe, North America, South America, and Australia. Planned recruitment consists of 100 MS-ON, 50 AQP4-IgG+ON, and 50 MOG-IgG+ON. This prospective, multimodal data collection will assess the potential value of early high-dose corticosteroid treatment, investigate the interrelations between functional impairments and structural changes, and evaluate the diagnostic yield of laboratory biomarkers. This analysis has the ability to substantially improve treatment strategies and the accuracy of diagnostic stratification in acute demyelinating ON

The unfinished agenda of communicable diseases among children and adolescents before the COVID-19 pandemic, 1990-2019: a systematic analysis of the Global Burden of Disease Study 2019

BACKGROUND: Communicable disease control has long been a focus of global health policy. There have been substantial reductions in the burden and mortality of communicable diseases among children younger than 5 years, but we know less about this burden in older children and adolescents, and it is unclear whether current programmes and policies remain aligned with targets for intervention. This knowledge is especially important for policy and programmes in the context of the COVID-19 pandemic. We aimed to use the Global Burden of Disease (GBD) Study 2019 to systematically characterise the burden of communicable diseases across childhood and adolescence. METHODS: In this systematic analysis of the GBD study from 1990 to 2019, all communicable diseases and their manifestations as modelled within GBD 2019 were included, categorised as 16 subgroups of common diseases or presentations. Data were reported for absolute count, prevalence, and incidence across measures of cause-specific mortality (deaths and years of life lost), disability (years lived with disability [YLDs]), and disease burden (disability-adjusted life-years [DALYs]) for children and adolescents aged 0-24 years. Data were reported across the Socio-demographic Index (SDI) and across time (1990-2019), and for 204 countries and territories. For HIV, we reported the mortality-to-incidence ratio (MIR) as a measure of health system performance. FINDINGS: In 2019, there were 3·0 million deaths and 30·0 million years of healthy life lost to disability (as measured by YLDs), corresponding to 288·4 million DALYs from communicable diseases among children and adolescents globally (57·3% of total communicable disease burden across all ages). Over time, there has been a shift in communicable disease burden from young children to older children and adolescents (largely driven by the considerable reductions in children younger than 5 years and slower progress elsewhere), although children younger than 5 years still accounted for most of the communicable disease burden in 2019. Disease burden and mortality were predominantly in low-SDI settings, with high and high-middle SDI settings also having an appreciable burden of communicable disease morbidity (4·0 million YLDs in 2019 alone). Three cause groups (enteric infections, lower-respiratory-tract infections, and malaria) accounted for 59·8% of the global communicable disease burden in children and adolescents, with tuberculosis and HIV both emerging as important causes during adolescence. HIV was the only cause for which disease burden increased over time, particularly in children and adolescents older than 5 years, and especially in females. Excess MIRs for HIV were observed for males aged 15-19 years in low-SDI settings. INTERPRETATION: Our analysis supports continued policy focus on enteric infections and lower-respiratory-tract infections, with orientation to children younger than 5 years in settings of low socioeconomic development. However, efforts should also be targeted to other conditions, particularly HIV, given its increased burden in older children and adolescents. Older children and adolescents also experience a large burden of communicable disease, further highlighting the need for efforts to extend beyond the first 5 years of life. Our analysis also identified substantial morbidity caused by communicable diseases affecting child and adolescent health across the world. FUNDING: The Australian National Health and Medical Research Council Centre for Research Excellence for Driving Investment in Global Adolescent Health and the Bill & Melinda Gates Foundation

Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BackgroundDisorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021.MethodsWe estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined.FindingsGlobally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer.InterpretationAs the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

The Impact of SARS-CoV-2 Pandemic Lockdown on a Botulinum Toxin Outpatient Clinic in Germany

Botulinum neurotoxin type A (BoNT/A) injections have to be administered repeatedly to achieve a rather stable, high level of improvement. This study aimed to take a look at changes in the daily routine of a BoNT/A outpatient clinic due to the SARS-CoV-2 pandemic lockdown, analyze the impact of SARS-CoV-2-induced re-injection delay on outcomes in patients with cervical dystonia (CD) (n = 36) and four other disease entities (n = 58), and study the influence of covariables, including previous injections and doses. For the present observational study, the first 100 patients who were scheduled to have an appointment between April 20 and May 18 during the partial lockdown and also had been treated regularly before the lockdown were recruited. Clinical and demographical characteristics and treatment-related data from the previous visits were extracted from charts. Time delay, symptom severity assessment, and TSUI score (if applicable) were gathered at the first coronavirus pandemic lockdown emergency visit for each patient. Of the 94 patients who could come to the clinic, 48 reported a delay and 44 reported worsening during the delay. Delays ranged from 1 to 63 days, the mean delay was 23 days, and the mean worsening was 26% compared to the previous visit. A significant correlation was found between the duration of the delay and the patient’s rating of worsening (PwP). In CD patients, the physician´s rating of CD worsening by the TSUI score (ATUSI-PTSUI) was significantly correlated with general worsening (DwP) and the TSUI at the last visit (PTSUI). A small delay of a few weeks led to a similar worsening of symptoms in CD and all other disease entities and to relapse on a higher level of severity. This relapse can only be compensated by continuous treatment up to at least 1 year until patients reach the same level of treatment efficacy as that before the SARS-CoV-2 pandemic

Effective Treatment of Neurological Symptoms with Normal Doses of Botulinum Neurotoxin in Wilson’s Disease: Six Cases and Literature Review

Recent cell-based and animal experiments have demonstrated an effective reduction in botulinum neurotoxin A (BoNT/A) by copper. Aim: We aimed to analyze whether the successful symptomatic BoNT/A treatment of patients with Wilson’s disease (WD) corresponds with unusually high doses per session. Among the 156 WD patients regularly seen at the outpatient department of the university hospital in Düsseldorf (Germany), only 6 patients had been treated with BoNT/A during the past 5 years. The laboratory findings, indications for BoNT treatment, preparations, and doses per session were extracted retrospectively from the charts. These parameters were compared with those of 13 other patients described in the literature. BoNT/A injection therapy is a rare (<4%) symptomatic treatment in WD, only necessary in exceptional cases, and is often applied only transiently. In those cases for which dose information was available, the dose per session and indication appear to be within usual limits. Despite the evidence that copper can interfere with the botulinum toxin in preclinical models, patients with WD do not require higher doses of the toxin than other patients with dystonia

Clinical Relevance of Neutralizing Antibodies in Botulinum Neurotoxin Type A

The precise definition of prevalence of neutralizing antibodies (NABs) affords cross-sectional testing of a cohort. But in most studies, only selected patients are tested. This leads to gross underestimation of NAB-prevalence, and the opinion that induction of NABs is a rare phenomenon in botulinum neurotoxin (BoNT)/A-therapy. However, recent cross-sectional studies report annual incidences between 1 and 2% in patients being treated with a complex protein (CP)-containing preparation. This implies that NAB-prevalence above 10% has to be expected in patients being treated for more than 10 years. High dose per session and long duration of treatment are relevant risk factors for induction of NABs. In patients exclusively treated with the CP-free incobotulinumtoxin A (incoBoNT/A) preparation Xeomin® no NAB-induction has been reported so far. In patients with NABs switching to incoBoNT/A may lead to a decline of NAB-titers. In patients with NABs under treatment with a CP-containing BoNT/A-preparation it may take years of treatment until a second treatment failure (STF) becomes clinical manifest. In a cohort of 59 patients with partial STF patients’ reports on the reduction of BoNT-activity predicted the presence of NABs better than treatment related data produced by the treating physicians