Morphometric network-based abnormalities correlate with psychiatric comorbidities and gene expression in PCDH19-related developmental and epileptic encephalopathy.

Protocadherin-19 (PCDH19) developmental and epileptic encephalopathy causes an early-onset epilepsy syndrome with limbic seizures, typically occurring in clusters and variably associated with intellectual disability and a range of psychiatric disorders including hyperactive, obsessive-compulsive and autistic features. Previous quantitative neuroimaging studies revealed abnormal cortical areas in the limbic formation (parahippocampal and fusiform gyri) and underlying white-matter fibers. In this study, we adopted morphometric, network-based and multivariate statistical methods to examine the cortex and substructure of the hippocampus and amygdala in a cohort of 20 PCDH19-mutated patients and evaluated the relation between structural patterns and clinical variables at individual level. We also correlated morphometric alterations with known patterns of PCDH19 expression levels. We found patients to exhibit high-significant reductions of cortical surface area at a whole-brain level (left/right pvalue = 0.045/0.084), and particularly in the regions of the limbic network (left/right parahippocampal gyri pvalue = 0.230/0.016; left/right entorhinal gyri pvalue = 0.002/0.327), and bilateral atrophy of several subunits of the amygdala and hippocampus, particularly in the CA regions (head of the left CA3 pvalue = 0.002; body of the right CA3 pvalue = 0.004), and differences in the shape of hippocampal structures. More severe psychiatric comorbidities correlated with more significant altered patterns, with the entorhinal gyrus (pvalue = 0.013) and body of hippocampus (pvalue = 0.048) being more severely affected. Morphometric alterations correlated significantly with the known expression patterns of PCDH19 (rvalue = -0.26, pspin = 0.092). PCDH19 encephalopathy represents a model of genetically determined neural network based neuropsychiatric disease in which quantitative MRI-based findings correlate with the severity of clinical manifestations and had have a potential predictive value if analyzed early.

Morphometry and network-based atrophy patterns in SCN1A-related Dravet syndrome.

Mutations of the voltage-gated sodium channel SCN1A gene (MIM#182389) are among the most clinically relevant epilepsy-related genetic mutations and present variable phenotypes, from the milder genetic epilepsy with febrile seizures plus to Dravet syndrome, a severe developmental and epileptic encephalopathy. Qualitative neuroimaging studies have identified malformations of cortical development in some patients and mild atrophic changes, partially confirmed by quantitative studies. Precise correlations between MRI findings and clinical variables have not been addressed. We used morphometric methods and network-based models to detect abnormal brain structural patterns in 34 patients with SCN1A-related epilepsy, including 22 with Dravet syndrome. By measuring the morphometric characteristics of the cortical mantle and volume of subcortical structures, we found bilateral atrophic changes in the hippocampus, amygdala, and the temporo-limbic cortex (P-value < 0.05). By correlating atrophic patterns with brain connectivity profiles, we found the region of the hippocampal formation as the epicenter of the structural changes. We also observed that Dravet syndrome was associated with more severe atrophy patterns with respect to the genetic epilepsy with febrile seizures plus phenotype (r = -0.0613, P-value = 0.03), thus suggesting that both the underlying mutation and seizure severity contribute to determine atrophic changes.

Can percussive intrapulmonary ventilation improve the efficacy of physiotherapy in children with cystic fibrosis?

Lung disease in cystic fibrosis (CF) is characterized by reduced mucociliary clearance, airway plugging, recurrent infections, and chronic pulmonary inflammation. Patients who are affected undergo daily respiratory physiotherapy to improve airway clearance. Intrapulmonary percussive ventilation (IPV) is a technique used in clinical practice, but it is not commonly used in CF patients. Evidence for various respiratory pathologies, particularly in children, is still lacking. We present the case of an 11-year-old boy with cystic fibrosis who did not respond to traditional respiratory physiotherapy techniques. We proposed and tested the use of IPV during hospitalization. In this case, the use of IPV in physiotherapy treatment reduced the need for intravenous antibiotics, hospitalization, and improved radiologic features. IPV can be used successfully in CF patients who are resistant to traditional physiotherapy techniques.

Loculated hydrocephalus: is neuroendoscopy effective and safe? A 90 patients' case series and literature review.

INTRODUCTION: Loculated hydrocephalus is a complex condition in which different non-communicating compartments form within the ventricular system due to different etiology, mainly intraventricular hemorrhage and infection. Since the end of the twentieth century, neuroendoscopy has been explored as a therapeutic option for loculated hydrocephalus with non-univocal results. METHODS: We performed a retrospective analysis of 90 patients who underwent endoscopic treatment for loculated hydrocephalus from January 1997 to January 2021 (mean age: 2 years, range 7-21). We included 37 (41.1%) children with multiloculated hydrocephalus, 37 (41.1%) with isolated lateral ventricle, 13 (14.4%) with excluded temporal horn, and 3 (3.3%) with isolated fourth ventricle. We compared our results with those available in literature. RESULTS: A mean of 1.91 endoscopic procedure/patient were performed (only one endoscopy in 42.2% of cases). Complications of neuroendoscopy and of shunt surgeries were recorded in 17 (18.9%) and 52 (57.8%) children, respectively. Twenty-six (28.9%) children were shunt-free at the last follow-up, 47.8% have only one shunt. DISCUSSION: The first goal of neuroendoscopy is to increase the rate of shunt-free patients but, when it is not possible, it aims at simplifying shunt system and reducing the number of surgical procedures. In our series, neuroendoscopy was able to achieve both these goals with an acceptable complication rate. Thus, our results confirmed neuroendoscopy as a valid tool in the long-term management of loculated hydrocephalus. Neuronavigation and intraoperative ultrasound could increase the success rate in cases with distorted anatomy.

Clinical Features, Neuropathology, and Surgical Outcome in Patients With Refractory Epilepsy and Brain Somatic Variants in the SLC35A2 Gene.

BACKGROUND AND OBJECTIVES: The SLC35A2 gene, located at chromosome Xp11.23, encodes for a uridine diphosphate-galactose transporter. We describe clinical, genetic, neuroimaging, EEG, and histopathologic findings and assess possible predictors of postoperative seizure and cognitive outcome in 47 patients with refractory epilepsy and brain somatic SLC35A2 gene variants. METHODS: This is a retrospective multicenter study where we performed a descriptive analysis and classical hypothesis testing. We included the variables of interest significantly associated with the outcomes in the generalized linear models. RESULTS: Two main phenotypes were associated with brain somatic SLC35A2 variants: (1) early epileptic encephalopathy (EE, 39 patients) with epileptic spasms as the predominant seizure type and moderate to severe intellectual disability and (2) drug-resistant focal epilepsy (DR-FE, 8 patients) associated with normal/borderline cognitive function and specific neuropsychological deficits. Brain MRI was abnormal in all patients with EE and in 50% of those with DR-FE. Histopathology review identified mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy in 44/47 patients and was inconclusive in 3. The 47 patients harbored 42 distinct mosaic SLC35A2 variants, including 14 (33.3%) missense, 13 (30.9%) frameshift, 10 (23.8%) nonsense, 4 (9.5%) in-frame deletions/duplications, and 1 (2.4%) splicing variant. Variant allele frequencies (VAFs) ranged from 1.4% to 52.6% (mean VAF: 17.3 ± 13.5). At last follow-up (35.5 ± 21.5 months), 30 patients (63.8%) were in Engel Class I, of which 26 (55.3%) were in Class IA. Cognitive performances remained unchanged in most patients after surgery. Regression analyses showed that the probability of achieving both Engel Class IA and Class I outcomes, adjusted by age at seizure onset, was lower when the duration of epilepsy increased and higher when postoperative EEG was normal or improved. Lower brain VAF was associated with improved postoperative cognitive outcome in the analysis of associations, but this finding was not confirmed in regression analyses. DISCUSSION: Brain somatic SLC35A2 gene variants are associated with 2 main clinical phenotypes, EE and DR-FE, and a histopathologic diagnosis of MOGHE. Additional studies will be needed to delineate any possible correlation between specific genetic variants, mutational load in the epileptogenic tissue, and surgical outcomes.

Early Effects of Elexacaftor-Tezacaftor-Ivacaftor Therapy on Magnetic Resonance Imaging in Patients with Cystic Fibrosis and Advanced Lung Disease.

This is a prospective, observational study involving three Cystic Fibrosis (CF) adult patients, evaluating the changes in chest magnetic resonance imaging (MRI) three months after the start of elexacaftor/tezacaftor and ivacaftor therapy. MRI showed a drastic reduction in mucus plugging and bronchial wall thickening, with an improvement in the diffusion-weighted MRI score. Similarly, a marked improvement in spirometric parameters, nutritional status, and sweat chloride was observed. Our preliminary data confirm that chest MRI could be a useful tool to assess disease progression in CF patients on modulatory drug therapy.

State-of-the-art review of lung imaging in cystic fibrosis with recommendations for pulmonologists and radiologists from the "iMAging managEment of cySTic fibROsis" (MAESTRO) consortium.

OBJECTIVE: Imaging represents an important noninvasive means to assess cystic fibrosis (CF) lung disease, which remains the main cause of morbidity and mortality in CF patients. While the development of new imaging techniques has revolutionised clinical practice, advances have posed diagnostic and monitoring challenges. The authors aim to summarise these challenges and make evidence-based recommendations regarding imaging assessment for both clinicians and radiologists. STUDY DESIGN: A committee of 21 experts in CF from the 10 largest specialist centres in Italy was convened, including a radiologist and a pulmonologist from each centre, with the overall aim of developing clear and actionable recommendations for lung imaging in CF. An a priori threshold of at least 80% of the votes was required for acceptance of each statement of recommendation. RESULTS: After a systematic review of the relevant literature, the committee convened to evaluate 167 articles. Following five RAND conferences, consensus statements were developed by an executive subcommittee. The entire consensus committee voted and approved 28 main statements. CONCLUSIONS: There is a need for international guidelines regarding the appropriate timing and selection of imaging modality for patients with CF lung disease; timing and selection depends upon the clinical scenario, the patient's age, lung function and type of treatment. Despite its ubiquity, the use of the chest radiograph remains controversial. Both computed tomography and magnetic resonance imaging should be routinely used to monitor CF lung disease. Future studies should focus on imaging protocol harmonisation both for computed tomography and for magnetic resonance imaging. The introduction of artificial intelligence imaging analysis may further revolutionise clinical practice by providing fast and reliable quantitative outcomes to assess disease status. To date, there is no evidence supporting the use of lung ultrasound to monitor CF lung disease.

How radiology can help pulmonary tuberculosis diagnosis: analysis of 49 patients.

PURPOSE: To identify the most frequent radiological findings of pulmonary tuberculosis using CT of the chest, to determine those with the highest degree of correlation, and, if possible, to identify the most suggestive radiological findings for acid-fast bacilli (AFB) positive disease. MATERIALS AND METHODS: The radiological and clinical data of 49 patients submitted to CT during diagnosis were retrospectively analysed. The association between findings was assessed using Fisher's exact test, while correlation at CT scan was evaluated with the Spearman analysis. RESULTS: Bronchiectasis/bronchioloectasis (89.8%), nodule(s) (81.6%), tree-in-bud (TIB), and consolidation (79.6% each) figured among the most common parenchymal findings. Lymphadenopathy (26.5%) was the most common nodal finding. TIB and cavity showed the highest correlation (r = 0.577), followed by TIB and bronchi(olo)ectasis (r = 0.498), TIB and consolidation (r = 0.497), nodule(s), and ground glass opacity (r = 0.488). High correlation was found in only the seven most frequent parenchymal findings. Consolidation, TIB, and cavity were useful to predict the AFB stain positivity. CONCLUSIONS: Our series confirms the extreme heterogeneity of pulmonary tuberculosis. It also proves there are couple of findings which can drive us to the right diagnosis. While a triad of findings predicts AFB positivity, we have not found any predictive sign of AFB negativity; consequently, all patients with suspected imaging and clinical findings for TB should be isolated.

Changes in volume-corrected whole-lung density in smokers and former smokers during the ITALUNG screening trial.

PURPOSE: To evaluate with a volume-corrected whole-lung approach changes in lung density over 2 years consistent with progression of pulmonary emphysema in smokers and former smokers enrolled in the ITALUNG trial of lung cancer screening using low-dose computed tomography (LDCT). MATERIALS AND METHODS: A total of 103 subjects (mean age 63±4 y with a pack-year history of at least 20) underwent 2 whole-lung LDCT examinations 2 years apart. Visual assessment was made independently by 2 experienced observers on the initial LDCT examination with a 0 to 4 grading system for each of 6 regions (right and left upper, mid, and lower lung). The whole-lung 15th percentile of attenuation coefficient and relative area (RA) at -910 HU, both corrected to the individual lung volume (Perc15v and RA910v), were measured on the 2 LDCT examinations. The intrasubject variability of Perc15v and RA910v was previously determined in 32 other subjects of the trial examined using the same scanner and technique twice over a 3-month interval for suspicious nodules. RESULTS: The 2 operators agreed on the presence of mild to severe emphysema (visual score ≥1 in at least 1 region) at initial LDCT examination in 24 (23%) of the 103 subjects. Fifteen subjects (15%) showed a Perc15v change between the 2 examinations exceeding the lower 95% limit of agreement, indicating progression of emphysema with a mean difference in lung density of -14.7%±2.6%. Ten of the 15 were identified as showing emphysema progression by RA910v as well. No association was observed between progression of emphysema and visual evidence of emphysema at initial LDCT examination, smoking status, or pack-years at baseline, or intervening changes in smoking habits. CONCLUSION: Once variations in inspiratory lung volumes are taken into account, changes in lung density over 2 years consistent with progression of pulmonary emphysema in elderly smokers and former smokers are uncommon.

Defining the intra-subject variability of whole-lung CT densitometry in two lung cancer screening trials.

RATIONALE AND OBJECTIVES: To define a statistically based variation of individual whole-lung densitometry above which a real increase of pulmonary extent can be suspected in lung cancer screening trials. MATERIALS AND METHODS: Baseline and 3-month follow-up low-dose computed tomography (LDCT) examinations of 131 smokers or former smokers recruited in the ITALUNG (32 subjects) and MILD (99 subjects) trials were compared using for each data set two different image processing tools for whole-lung densitometry. Both trials were approved by institutional review boards, and written informed consent was obtained from all participants. Assuming that no change of emphysema extent can occur in a 3-month interval, the Bland and Altman method was used to assess the agreement between baseline and follow-up LDCT examinations for lung volume, 15th percentile (Perc15) of lung density and Perc15 corrected for lung volume by application of a linear detrend on log-transformed data. RESULTS: Similar results were obtained in each data set using two different image processing tools. In the ITALUNG cohort the 95% limits of agreement (LoA) interval of volume corrected Perc15 was -9.7 to 10.7% using image processing method 1 and -10.3 to 11.5% using image processing method 2. In the MILD cohort, the 95% LoA interval of volume corrected Perc15 was -14.7 to 17.3% with both image processing methods. CONCLUSION: In the two considered lung cancer screening settings a range of 9.7-14.7% decrease of volume corrected Perc15 represents a statistically defined threshold to suspect a real increase of emphysema extent in serial LDCT examinations.