Chemoprevention for colorectal neoplasia has attracted growing interest, with multiple medications investigated. Metformin may decrease the overall incidence of cancer in patients with diabetes and may decrease the incidence of colorectal cancer. We aimed to determine the impact of metformin use on the behavior of colorectal adenomas in a US veteran population. All patients with at least two high-quality colonoscopies between January 1997 and December 2013 at Veterans Affairs New York Harbor Healthcare System were identified. Outpatient prescription records were used to determine metformin exposure, and colonoscopy findings were recorded. Multivariable logistic regression was used to determine factors associated with adenoma detection on baseline and interval colonoscopy. In total, 1869 patients with two successive colonoscopies (median 4.5 years) were included. Four hundred and sixty patients had metformin exposure prior to baseline and/or interval colonoscopy. Overall adenoma detection rate was 59.7% at baseline and 45.9% at interval colonoscopy. On multivariable analysis, metformin use was associated with decreased adenoma prevalence at baseline (OR 0.68; 95% CI 0.51–0.92; p = 0.015). Metformin did not impact adenoma incidence at interval colonoscopy whether prescribed before baseline (OR 1.26; 95% CI 0.60–2.67), after baseline (OR 1.25; 95% CI 0.91–1.72), or before and after baseline (OR 1.14; 95% CI 0.82–1.58). In this retrospective analysis of an average-risk cohort, metformin use was associated with a decreased prevalence of colorectal adenomas at baseline colonoscopy. This inverse association did not persist on interval colonoscopy. Prospective studies are needed to evaluate potential chemoprotective effects of metformin over time.

Numerous studies showed that epilepsy represents a high burden in Tuberous Sclerosis Complex (TSC), affecting 63 to 78% of the patients. Epilepsy will be refractory to medication in over 60% of cases in early presentations, and accompanied by intellectual disabilities and/or autism spectrum disorders. The emerging experimental and clinical data suggest that the molecular and cellular changes triggered by seizures, particularly during the first weeks of life, can be limited by early action. Making any effort to avoid or delay epilepsy onset is a promising pathway to improve global outcome for TSC patients, although it is not possible to tidy up the specific roles of seizures, interictal abnormalities, and cortical abnormalities upon neurodevelopment. Early diagnosis of epilepsy can be made during a "symptomatic phase," shortly after the onset of seizures (focal seizures or spasms), revealing the TSC in a young infant. As soon as the diagnosis is made, a treatment with Vigabatrin is now recommended. The diagnosis of epilepsy can also be performed during a "presymptomatic phase", with the improvement of fetal and neonatal diagnosis of TSC. Recent studies demonstrated a significant delay of more than 3 months between the detection of EEG abnormalities and the first clinical seizures, which allows to consider a preventive treatment. Beside vigabatrin, mTOR inhibitors may have a place in this early management. The last recommendations about early detection and treatment of epilepsy in TSC will be detailed in this review. © 2022 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.

De précédentes études montrent qu’une partie conséquente des enfants ayant un trouble d’apprentissage présente également une anxiété. L’anxiété peut être primaire ou bien secondaire au trouble d’apprentissage. Concernant la dyslexie, les différentes prévalences observées dans la littérature montrent que 9,9 % à 25 % des enfants avec un trouble spécifique du langage écrit présentent de façon concomitante des signes d’anxiété. L’accompagnement pédagogique semble avoir un rôle conséquent dans cette anxiété et pourrait induire un effet protecteur dans son apparition ou son intensité. Notre étude a pour but de rapporter la proportion d’enfants anxieux parmi nos patients dyslexiques, d’observer s’il existe ou non un effet de l’âge, du niveau solaire ou du sexe sur cette anxiété, mais également d’examiner la quantité d’enfants pour laquelle un suivi psychologique a été conseillé. Un autre objectif de cette étude est d’appuyer la nécessité de l’accès au diagnostic et de l’instauration de mesures d’accompagnement. L’échantillon est constitué de 114 patients ayant reçu un diagnostic de dyslexie en centre de diagnostic. Les dossiers des patients sont analysés de façon rétrospective afin de rechercher les signes anxieux dans les éléments anamnestiques et dans l’observation du comportement des enfants lors des différents bilans réalisés lors de leur venue au centre. Nos patients dyslexiques sont 69 % à présenter des signes anxieux. Il n’y a pas de différence d’âge entre les patients anxieux et non anxieux, ni de différence en fonction du niveau scolaire (école primaire ou collège). Il existe un effet du sexe chez les enfants dyslexiques et anxieux : il y a moins d’anxiété chez les garçons dyslexiques que chez les filles dyslexiques. Un suivi psychologique a été conseillé pour 65 % des patients. La proportion d’enfants dyslexiques présentant également une anxiété est importante, c’est pourquoi il est nécessaire d’améliorer l’accès au diagnostic précoce, la connaissance et la prise en compte de ces troubles, ainsi que la mise en place des aides nécessaires (aménagements scolaires, accompagnement thérapeutique). Previous studies have shown that children with learning disabilities also have psychological symptoms such as anxiety. It is the most common psychological disorder and usually appears in childhood or adolescence. We focus on children with reading disabilities. As anxiety symptoms in dyslexic children, low self-esteem, loss of interest, fear of rejection, hostility, behavioural or concentration problems are described, these children report more somatic complaints than normal readers. This anxiety can be either primary or secondary to reading difficulties, with the presence of one triggering or aggravating the other. With regard to the prevalences found in the literature, 9.9% to 25% of children with reading impairment have an anxiety disorder associated with it. This can have a significant impact on academic achievement but also on professional integration. Few studies have analyzed the presence of anxiety in children with a specific reading disorder according to age or grade level. That is why we analyzed data of anxious children among patients with developmental dyslexia, and investigated a possible effect of age, school level (primary or secondary school) or gender. Finally, we also paid attention to the proportion of anxious children for whom psychological counselling was recommended. Another goal of this study was to support the need for access to diagnosis, and the implementation of accompanying measures. The sample consists of 114 patients admitted in a French referral center of learning disabilities and for whom a diagnosis of dyslexia had been established. A retrospective analysis of these children's files was carried out in order to identify the signs of anxiety. Initially, this study was based on the anamnesis carried out with the parents or guardians and then the child's behaviour during the various assessments carried out at the center was analyzed. Among our dyslexic patients, 69% also had anxiety. There was no age difference between anxious and non-anxious patients, nor was there a difference according to school level (primary or secondary school). There was a gender effect in dyslexic and anxious children with less anxiety in dyslexic boys than in dyslexic girls. Psychological counselling was advised for 65% of patients. A significant proportion of children with dyslexia have co-morbid anxiety, regardless of gender, age or class. This is why it is necessary to improve access to early diagnosis, knowledge and consideration of these disorders, as well as the implementation of necessary aids (school adjustments, therapeutic support).

Introduction: Esophageal actinomycosis is a rare type of esophageal infection and presents as erosions or ulcers under endoscopy. Here we present a 63-year-old woman who complains of dysphagia, with biopsy showing actinomyces infection but repeat biopsy revealed squamous cell carcinoma. Case Description/Methods: A 63-year-old Chinese female with a history of gastritis presented with solid food dysphagia and epigastric pain for over a month. The pain was not improved after proton pump inhibitors but was relieved by self-induced vomiting. Review of systems showed 10lb weight loss over a month with a recent history of self-resolved hematemesis. Prior esophagogastroduodenoscopy (EGD) and colonoscopy were normal 3 years ago. CT of the chest demonstrated a 1.7 cm circumferential mass in the mid-esophagus with luminal narrowing (Figure 1A). EGD discovered a friable soft circumferential mass 26-29 cm from the incisors that are not actively bleeding but covered with blood clots (Figure 1B). Biopsy showed esophageal mucosal ulceration and actinomyces infection. The patient was started on amoxicillin to treat actinomyces infection. Meanwhile, the patient underwent a repeat EGD for rebiopsy given concerns for malignancy, which resulted in poorly differentiated squamous cell carcinoma. Endoscopic ultrasonography (EUS) was performed for staging but was limited staged uT3N1Mx as the mass could not be traversed by echoendoscopy (Figure 1C). Later PET-CT illustrated locally advanced disease with atrium involvement (Figure 1D). The patient underwent neoadjuvant chemotherapy with carboplatin-taxol and radiation followed by esophagogastrectomy for curative intent. Discussion: Actinomyces are facultatively anaerobic, Gram-negative bacilli. They commensally live within the oral cavity and gastrointestinal tract. Most esophageal actinomyces (EA) infection was previously described to resemble esophagitis or esophageal ulcers, with the endoscopic description being extensive necrotic areas. EA typically presents with dysphagia and odynophagia, particularly in immunocompromised patients or with malignancies. Actinomyces species capitalize on tissue injury or mucosal breach to invade adjacent structures and spreads regardless of anatomical barrier, thus mimicking malignancy. In our case, the local tissue damage caused by neoplastic disease or irradiation predisposed the actinomyces infection. Clinicians need to have a high index of suspicion and clinical knowledge regarding its unusual presentations and ability to mimic malignancy.Figure 1.: A. CT of the chest demonstrated a 1.7 cm mass present in the mid-esophagus with lumen narrowing. B. A friable mass without active bleeding but covered with blood clots on endoscopy finding. C. Limited staged uT3N1Mx under EUS D. PET-CT showed locally advanced disease with atrium involvement.

CASE REPORT Cecal bascule is an exceedingly rare type of cecal volvulus in which a mobile cecum folds anteriorly and superiorly on to the ascending colon, causing obstruction. The following vignette highlights a case of cecal bascule after double-balloon-assisted colonoscopy. A 68-year-old man with a history of advanced adenoma and no prior abdominal surgery was admitted for surveillance colonoscopy after inability to intubate the cecum on outpatient colonoscopy. Repeat attempt using double-balloon-assisted colonoscopy on the next day failed to intubate the cecum, raising concern for cecal volvulus. During medical observation, the patient complained of abdominal distention, discomfort, and inability to pass flatus. Abdominal x-ray showed a significantly dilated ascending colon to 12 cm in diameter (Figure 1). Computed tomography revealed upside-down rotated cecum with the ileocecal valve pointing laterally and dilatation of ascending colon to 10 cm without evidence of perforation, compatible with cecal volvulus. A multidisciplinary discussion between gastroenterology, radiology, and surgery resulted in exploratory laparotomy with right hemicolectomy and end ileostomy. Intraoperatively, a redundant colon was observed with severely dilated cecum and cecal bascule with pathology showing distended cecum and part of the right colon with vascular congestion, suggestive of mild acute ischemic colitis (Figure 1). On follow-up, the patient complained of abdominal pain without signs of obstruction.Figure 1.: Abdominal x-ray and exploratory laparotomy findings. (A) Abdominal x-ray showed a significantly dilated colon. (B) Exploratory laparotomy revealed a rotated cecum with a severely dilated colon.Cecal volvulus is a rare clinical entity, which accounts for 1%–2% of all large bowel obstructions.1 Cecal bascule, where the distended cecum folds anteriorly on the ascending colon without torsion, is the rarest type of cecal volvulus, accounting for 5%–20% of all cases.2 It occurs secondary to congenital or acquired adhesions fixing the anterior wall of the cecum to the ascending colon. In our patient, the increased motility of the cecal volvulus combined with the insertion of double-balloon-assisted colonoscopy with air insufflation may have initiated the rotation of the cecum. The signs and symptoms of a cecal bascule are similar to cecal volvulus. Plain x-ray usually reveals a distended cecum. Abdominal computed tomography confirms the diagnosis in 90% of patients showing upward folding of the cecum, as in our patient. Treatment is primarily surgical. Owing to high recurrence after simple reduction, cecopexy or resection and anastomosis are preferred approaches.3 In patients with recurrent or persistent abdominal pain and distension, cecal bascule should be considered in the differential diagnosis. DISCLOSURES Author contributions: T. Li wrote, edited, and approved the article. Y. Myat wrote and approved the article. ST Nguyen revised the article for intellectual content. W. Zhao provided the endoscopy images. P. Patel provided the pathology images. M. Martinez approved the final article and is the article guarantor. Financial disclosures: None to report. Previous presentation: This case was presented at the American College of Gastroenterology Annual Scientific Meeting; October 22–27, 2021; Las Vegas, NV. Informed consent could not be obtained for this case report. All identifying information has been removed.

Introduction: Cecal bascule is an exceedingly rare type of cecal volvulus in which a mobile cecum folds anteriorly and superiorly on to the ascending colon, causing partial obstruction. The following vignette highlights a case of cecal bascule following two unsuccessful colonoscopy attempts. Case Description/Methods: A 68-year-old male with history of advanced adenoma and no prior abdominal surgery was admitted for surveillance colonoscopy after inability to intubate the cecum on outpatient colonoscopy. Repeat double balloon assisted colonoscopy attempt failed to intubate the cecum , raising concern for cecal volvulus. While admitted, the patient complained of abdominal distention and discomfort despite ability to pass gas and stool. Abdominal x-ray showed a significantly dilated colon to 12 centimeters (Figure 1A). Computed tomography (CT) revealed upside down rotated cecum with ileocecal valve pointing laterally, dilatation of ascending colon to 10 centimeters without evidence of perforation, compatible with cecal volvulus (Figure 1B). A multi-disciplinary discussion between gastroenterology, radiology, and surgery resulted in exploratory laparotomy with right hemicolectomy and end ileostomy. Intraoperatively, a redundant colon was observed with severely dilated cecum and cecal bascule. He underwent a right hemicolectomy with ileal colonic anastomosis. The patient did well post-surgery without significant sequelae. Discussion: Cecal volvulus, a rare clinical entity, accounts for 1-2% of all large bowel obstructions. Cecal bascule, where the distended cecum folds anteriorly on the ascending colon without torsion, is the rarest type of cecal volvulus, accounting for 5-20% of all cases. It occurs secondary to congenital or acquired adhesions fixing the anterior wall of the cecum to that of the ascending colon. In our patient, the increased motility related to the colonoscopy preparation may have initiated the rotation of the cecum. The signs and symptoms of a cecal bascule are similar to that of a cecal volvulus. Plain X-ray usually reveals a distended cecum. CT of abdomen confirms the diagnosis in 90% of patients showing upward folding of the cecum, as in our patient. Treatment is primarily surgical. Due to high recurrence after simple reduction, cecopexy or resection and anastomosis are preferred approaches. In patients with recurrent or persistent abdominal pain and distension, cecal bascule should be considered in the differential diagnosis.Figure 1.: Abdominal X-ray and exploratory laparotomy findings.

Introduction: Two tumors having different histopathologies at anatomically distinct sites giving the picture of dual primary malignancies. Here we presented a case of two possible primary tumors and one secondary mass. Case Report: A 74-year-old female, active smoker, without personal or family cancer history presented with early satiety and weakness for two months. Systems review was positive for a “raw” feeling in stomach, alleviated with antacids. Vital signs were stable with a negative abdominal exam. Lab showed leukocytosis 24.8 K/uL (3.5–10.8 K/uL) with left shift, microcytic anemia with hemoglobin 6.1 g/dL (12.0–16.0 g/dL), and reactive thrombocytosis 477 K/uL (130–400 K/uL). Contrast-enhanced computed tomography (CT) showed right upper lobe necrotizing cavitating lesion with reactive mediastinal and right hilar lymphadenopathy, two irregular hypodense lesions in pancreatic head and tail without ductal dilation with two irregular hypodense liver lesions. Immunohistochemistry of lung and pancreatic lesions were biopsied through endoscopic ultrasound (EUS), consistent with poorly differentiated squamous cell carcinoma (SCC) with extensive necrosis, which indicates pancreatic masses are likely metastases from the lung. Liver lesion biopsy exhibited high-grade neuroendocrine tumor (NET) with focal necrosis. Next gene sequencing was pursued. Given poor functional status, palliative immunotherapy was offered; however, the patient succumbed to respiratory failure. Conclusion: Given the morphology and immunoprofile, differential diagnosis includes dual primary cancers with one metastasis, or primary SCC with metastasis with neuroendocrine differentiation. Despite having different histopathology and immunophenotype, both lung and liver tumors harbor the same molecular profile even at the variants of unknown significance that show identical mutations. As a result, they are directly related. TP53, RB1, MYCL1, and MEK1 mutations are more prevalent in SCC than NET. Tumor mutation burden values may vary as the tumor clonal structure varies between primary and metastatic sites, with higher rates of monoclonal structure recorded in metastases due to clonal selection, leading to a reduction in overall genetic diversity (“bottlenecking”). This raises the suspicion that the liver tumor is a SCC with neuroendocrine differentiation. The paucity of the specimen and rapid clinical course limited further investigation. Germline testing would have been useful to determine whether these findings are somatic or germline.

Pragmatics can be defined as the way in which language is used to communicate in a given social context. Although there is a lack of a standardized assessment, healthcare professionals find themselves confronted with pragmatic language skill impairments in children with neurodevelopmental disorders or brain injuries. The characterization of language use causes problems in social interactions, which has clinical implications in daily life. However, this is still underestimated because there is currently no quick, easy-to-use screening device to rank these deficits. We have developed a pragmatic deficits screening chart that has been tested on a control population of children aged 6-12 years. The chart comprises 26 items exploring seven areas of pragmatics (intentionality, governance of exchange, organization of information, adaptation strategies, conversational implicit language, nonverbal skills, and paralinguistic aspects). Parents select one of four possible answers to describe how frequently their child demonstrates each type of behavior ("never, rarely, sometimes, often"). We distributed 1666 charts; 760 were returned, of which 552 could be analyzed. Internal consistency as measured with Cronbach's alpha coefficient (0.88) was satisfactory. There was no influence of age on total score, nor of the department/type of schooling. The population distribution was non-Gaussian so the results are presented in percentiles. We propose a first-line screening tool that is quick and easy to complete by family, which facilitates referral to specialists for further investigations into the etiological implications of pragmatic language impairment.

Les difficultés alimentaires sont fréquentes chez les patients atteints de handicap d’origine neurologique. Une dénutrition, un retard de croissance, un déficit en micronutriments et une ostéopénie peuvent compliquer l’évolution clinique de ces enfants particulièrement fragiles. Les manifestations digestives, incluant reflux gastro-œsophagien, constipation et dysphagie, sont également fréquentes et affectent leur qualité de vie et leur état nutritionnel. La prise en charge de ces problèmes digestifs et nutritionnels n’est actuellement pas systématisée. Un groupe de travail de 15 experts de la Société européenne de gastro-entérologie, hépatologie et nutrition pédiatrique (ESPGHAN) a récemment publié un guide pour leur prise en charge, dont cet article en rapporte les recommandations.

In this case report, we present a case of a likely paradoxical embolism in a young patient with no significant risk factor for coronary artery disease that initially presented with shortness of breath and bilateral calf pain that was found to have a deep vein thrombosis. There was a development of a pulmonary embolism that we believed due to right ventricular strain resulted in an embolus crossing into the arterial system via an intracardiac shunt causing a myocardial infarction via a distal occlusion of the right coronary artery. Patient was treated with full dose anticoagulation and a patent foramen ovale (PFO) closure was recommended. J Med Cases. 2017;8(11):365-367 doi: https://doi.org/10.14740/jmc2933w

Introduction: USPSTF recommends a screening colonoscopy for all average risk patients of age 50-75. Despite screening reducing the risks of colorectal cancer by 40%, it remains the second leading cause of death related to cancer in the US. Minority populations continue to show disproportionately lower screening rates, in addition to higher rates of cancer incidence and mortality. A retrospective review sought to investigate screening practices in an inner city cohort, identifying adherence levels to USPSTF recommendations and measuring the near miss incidence rate of patients who only received a first time colonoscopy for diagnostic, rather than screening purposes. Methods: A retrospective review at a major inner city teaching hospital was performed. Average risk first time screening colonoscopies over a 2-month period were analyzed. 122 charts were identified. Ages of males to females and African Americans (AA's) were compared to Non-AA's. Incidence of screening was also divided into age ranges of 50-54, 55-59, 60-64, 65-69 and 70-75, in line with the USPSTF screening recommendations of age 50-75 for individuals of average risk. In addition, the percentage of patients that underwent a screening colonoscopy only once experiencing gastrointestinal related symptoms was analyzed. Results: A total of 122 patients in the hospital service were analyzed. The average first time screening age for average risk AA's (n =70) was 59.34. Non-AA's (n=25) had an average age of 59.76. The average male (n=42) was 59.86 while the average female (n=53) was aged 59.38. By age range, 10% of all AA's received their colonoscopy at an age 70-75 (n=7), 19% (n=13) were aged 65-69, 16% (n=11) were aged 60-64, 21% (n=15) were aged 55-59, and 34% (n=24) were aged 50-54. Of non-AA's, 4% (n=1) received their colonoscopy at an age 70-75, 20% (n=5) were aged 65-69, 20% (n=5)were aged 60-64, 40% (10) were aged 55-59, and 16% (4) were aged 50-54. Conclusion: Disparities between the USPSTF colonoscopy screening recommendations and the observed screening practices were identified. There were no statistically significant differences in average first time colonoscopy age when stratifying for gender or race, implicating geo-socio-economics as a formidable risk factor and greater predictor of screening patterns than both race and gender. With lower rates of primary care physician enrollment in inner city communities already contributing to health screening disparities.

Introduction: The rising prevalence of obesity projects it to exceed cigarette smoking as the leading preventable cause of death in the US. Increasing evidence demonstrates a link between obesity and colorectal cancer. With minority populations carrying a disproportionate degree of incidence and mortality secondary to colorectal cancer, this study sought to examine the burden of modifiable risk factors within a predominantly African American (AA) cohort at a major inner city teaching hospital. Methods: All adults who had undergone a screening or diagnostic colonoscopy from 2013 to 2015 were included in this study. A total of 4359 patients were analysed after eliminating the duplicate data.The following variables, BMI categories, cigarette smoking status, ethnicity, Diabetes Mellitus and alcohol intake were analysed to examine if there were differences in risk factors (DM, smoking, BMI and alcohol) between these groups. Results: Our population consisted of 77.3% AA. The prevalence of obesity, BMI ≥ 30, in this cohort, was 44.9%. 44.8% with DM, 19.7% current smokers and 31.1% reporting alcohol consumption. 40 subjects (0.9%) were diagnosed with CRC over the 3 year period. Subjects were more likely to be obese or overweight (77.1%). AA in this population were more likely to be overweight and obese (OR-1.25, 95% CI- 1.06 - 1.47) and to consume alcohol products (OR- 1.45; 95% CI- 1.23 - 1.70) There was no statistical differences in smoking status and DM in AA. In the analysis of predictors of CRC in the study population, gender was independently associated with the development of CRC, with females being less likely to be diagnosed by almost half (OR- 0.45: 95% CI- 0.23- 0.86). When adjusted for all the other predictors including increasing. There was still a statistically significant association between gender, females vs males (OR- 0.46; 95% CI; 0.23- 0.93) and increasing age (OR- 1.06, 95% CI; 1.02- 1.10). Conclusion: Overall incidence of CRC was higher in this population compared to US averages. AA were more likely to have a greater burden of modifiable risk factors (BMI>25 and alcohol intake), but these factors did not significantly predict risk of CRC. It is possible that in low socioeconomic cohorts, other unmeasured confounders like diet and environmental factors may play a greater role as modifiable risk factors than obesity and DM. This study highlights the striking prevalence and additional burden of modifiable risk factors in an underserved, predominantly AA cohort.

The definition of a pre and postfixed brachial plexus is varied in the literature, which results in inconsistent conclusions for various studies. As anatomical variation is important both during clinical evaluation and surgical procedures of the brachial plexus, a review of this literature was performed. Based on our review, variation in the contribution to the brachial plexus is more the rule than the exception. These variations may lead to deviation from the expected dermatome distribution as well as differences in the motor innervation of muscles of the upper limb. Such variations may predispose patients to certain pathology such as thoracic outlet syndrome and may alter surgical approaches to the brachial plexus.

A defining histopathologic feature of Taylor-type cortical dysplasia (CD) is the presence of cytomegalic neurons and balloon cells. Most cytomegalic neurons appear to be pyramidal-shaped and glutamatergic. The present study demonstrates the presence of cytomegalic GABAergic interneurons in a subset of pediatric patients with severe CD. Cortical tissue samples from children with mild, severe, and non-CD pathologies were examined using morphologic and electrophysiologic techniques. By using in vitro slices, cytomegalic cells with characteristics consistent with interneurons were found in 6 of 10 patients with severe CD. Biocytin labeling demonstrated that cytomegalic interneurons had more dendrites than normal-appearing interneurons. Whole-cell patch clamp recordings showed that cytomegalic interneurons had increased membrane capacitance and time constant compared with normal-appearing interneurons. They also displayed signs of cellular hyperexcitability, evidenced by increased firing rates, decreased action potential inactivation, and the occurrence of spontaneous membrane depolarizations. Single-cell reverse transcription-polymerase chain reaction and immunohistochemistry for GABAergic markers provided further evidence that these cells were probably cytomegalic interneurons. The pathophysiologic significance of GABAergic cytomegalic interneurons in severe CD tissue is unknown, but they could inhibit glutamatergic cytomegalic pyramidal neurons, or contribute to the synchronization of neuronal networks and the propagation of ictal activity in a subset of pediatric patients with severe CD.

Objective: In children with and without infantile spasms, this study determined brain volumes and cell densities in epilepsy surgery patients with tuberous sclerosis complex (TSC) and cortical dysplasia with balloon cells (CD). Methods: We compared TSC (n = 18) and CD (n = 17) patients with normal/autopsy controls (n = 20) for MRI gray and white matter volumes and neuronal nuclei (NeuN) cell densities. Results: In patients without a history of infantile spasms, TSC cases showed decreased gray and white matter volumes (-16%). In cases with a history of infantile spasms, both CD (-25%) and TSC (-35%) patients showed microencephaly. This was confirmed in monozygotic twins with TSC, where the twin with a history of spasms had cerebral volumes less (-16%) than the twin without a history of seizures. Regardless of seizure history, TSC patients showed decreased NeuN cell densities in lower gray matter (-36%), whereas CD patients had increased densities in upper cortical (-52%) and white matter regions (-65%). For TSC patients, decreased lower gray matter NeuN densities correlated with reduced MRI volumes. Conclusions: Patients with tuberous sclerosis without spasms showed microencephaly associated with decreased cortical neuronal densities. In contrast, cortical dysplasia patients without spasms were normocephalic with increased cell densities. This supports the concept that tuberous sclerosis and cortical dysplasia have different pathogenetic mechanisms despite similarities in refractory epilepsy and postnatal histopathology. Furthermore, a history of infantile spasms was associated with reduced cerebral volumes in both cortical dysplasia and tuberous sclerosis patients, suggesting that spasms or their treatment may contribute to microencephaly independent of etiology.

A new method for enhancing MRI contrast between gray matter (GM) and white matter (WM) in epilepsy surgery patients with symptomatic lesions is presented. This method uses the radiation damping feedback interaction in high-field MRI to amplify contrast due to small differences in resonance frequency in GM and WM corresponding to variations in tissue susceptibility. High-resolution radiation damping-enhanced (RD) images of in vitro brain tissue from five patients were acquired at 14 T and compared with corresponding conventional T(1)-, T(2) (*)-, and proton density (PD)-weighted images. The RD images yielded a six times better contrast-to-noise ratio (CNR = 44.8) on average than the best optimized T(1)-weighted (CNR = 7.92), T(2) (*)-weighted (CNR = 4.20), and PD-weighted images (CNR = 2.52). Regional analysis of the signal as a function of evolution time and initial pulse flip angle, and comparison with numerical simulations confirmed that radiation damping was responsible for the observed signal growth. The time evolution of the signal in different tissue regions was also used to identify subtle changes in tissue composition that were not revealed in conventional MR images. RD contrast is compared with conventional MR methods for separating different tissue types, and its value and limitations are discussed.

In epilepsy patients with cortical dysplasia (CD), this study determined the probable ontogenetic timing of pathogenesis based on the number, location and appearance of neurons. Magnetic resonance imaging (MRI) determined gray and white matter volumes of affected and non-affected cerebral hemispheres, and gray and white matter neuronal-nuclear protein (NeuN) densities and sizes were assessed in epilepsy surgery patients (0.2-38 years) with CD (n = 25) and non-CD etiologies (n = 14), and compared with autopsy cases (n = 13; 0-33 years). Pathology group, seizure type and age at surgery were compared against MRI and NeuN data. CD patients demonstrated increased MRI cerebral (3%) and gray matter (8%) volumes of the affected compared with non-affected cerebral hemisphere, and increased layer 1 (131%), upper cortical (9-23%) and white matter (28-77%) NeuN densities compared with autopsy cases. Non-CD cases showed decreased cerebral volumes of the affected hemisphere (14-18%) without changes in NeuN densities. Compared with autopsy cases, in CD and non-CD patients, cortical neurons were hypertrophied. Patients with a history of infantile spasms had a 40% increase in the size of layer 1 neurons compared with cases without spasms. By age, regardless of pathology group, there were logarithmic increases in MRI cerebral and white matter volumes, logarithmic increases in the size of lower gray and superficial white matter neurons, and logarithmic decreases in gray and white matter neuronal densities. These results support the concept that there were more neurons than expected in layer 1, gray, and white matter of CD patients compared with non-CD and autopsy cases. In addition, the location and appearance of neurons are consistent with the hypothesis that CD is the consequence of abnormalities occurring late in corticoneurogenesis that involve excessive neurogenesis with retention of pre-plate cells in the molecular layer and subplate regions.

In paediatric epilepsy surgery patients with hemimegalencephaly (HME; n = 23), this study compared clinical, neuroimaging and pathologic features to discern potential mechanisms for suboptimal post-hemispherectomy developmental outcomes and structural pathogenesis. MRI measured affected and non-affected cerebral hemisphere volumes for HME and non-HME cases, including monozygotic twins where one sibling had HME. Staining against neuronal nuclei (NeuN) determined grey and white matter cell densities and sizes in HME and autopsy cases, including the non-affected side of a HME surgical/autopsy case. By MRI, the affected hemisphere was larger and the non-affected side smaller in HME compared with non-HME children. The affected HME side showed enlarged abnormal deep grey and white matter structures and/or T-2-weighted hypointensity in the subcortical white matter in 75% of cases, suggestive of excessive pre-natal neurogenesis and heterotopias. Histopathological examination of the affected HME side revealed immature-appearing neurons in 70%, polymicrogyria (PMG) in 61% and balloon cells in 45% of cases. Compared with autopsy cases, in HME children NeuN cell densities on the affected side were increased in the molecular layer and upper cortex (+244 to +18%), decreased in lower cortical layers (-35%) and increased in the white matter (+139 to +149%). Deep grey matter MRI abnormalities and/or T-2-weighted white matter hypointensity correlated with the presence of immature-appearing neurons and PMG on histopathology, decreased NeuN cell densities in lower cortical layers and a positive history of infantile spasms. Post-surgery seizure control was associated with decreased NeuN densities in the molecular layer. In young children with HME and epilepsy, these findings indicate that there are bilateral cerebral hemispheric abnormalities and contralateral hemimicrencephaly is a likely explanation for poorer post-surgery seizure control and cognitive outcomes. In addition, our findings support the hypothesis that HME pathogenesis probably involves somatic mutations that affect each developing cerebral hemisphere differently with more neurons than expected on the HME side.

Seizures in cortical dysplasia (CD) could be from cytomegalic neurons and balloon cells acting as epileptic ‘pacemakers’, or abnormal neurotransmission. This study examined these hypotheses using in vitro electrophysiological techniques to determine intrinsic membrane properties and spontaneous glutamatergic and GABAergic synaptic activity for normal-pyramidal neurons, cytomegalic neurons and balloon cells from 67 neocortical sites originating from 43 CD patients (ages 0.2–14 years). Magnetic resonance imaging (MRI), 18fluoro-2-deoxyglucose positron emission tomography (FDG-PET) and electrocorticography graded cortical sample sites from least to worst CD abnormality. Results found that cytomegalic neurons and balloon cells were observed more frequently in areas of severe CD compared with mild or normal CD regions as assessed by FDG-PET/MRI. Cytomegalic neurons (but not balloon cells) correlated with the worst electrocorticography scores. Electrophysiological recordings demonstrated that cytomegalic and normal-pyramidal neurons displayed similar firing properties without intrinsic bursting. By contrast, balloon cells were electrically silent. Normal-pyramidal and cytomegalic neurons displayed decreased spontaneous glutamatergic synaptic activity in areas of severe FDG-PET/MRI abnormalities compared with normal regions, while GABAergic activity was unaltered. In CD, these findings indicate that cytomegalic neurons (but not balloon cells) might contribute to epileptogenesis, but are not likely to be ‘pacemaker’ cells capable of spontaneous paroxysmal depolarizations. Furthermore, there was more GABA relative to glutamate synaptic neurotransmission in areas of severe CD. Thus, in CD tissue alternate mechanisms of epileptogenesis should be considered, and we suggest that GABAergic synaptic circuits interacting with cytomegalic and normal-pyramidal neurons with immature receptor properties might contribute to seizure generation.