Israel Medical Association Journal

Uveitis is an inflammatory disorder of the uveal tract of the eye that can affect both adults and children. Non-infectious uveitis can be an expression of a systemic autoimmune condition, or it can be idiopathic. It is a serious disease, associated with possible severe complications leading to visual impairment and blindness. For this reason, a prompt diagnosis and assessment of an appropriate treatment, with the collaboration of specialists such as ophthalmologists and rheumatologists, are extremely important. Many treatment options may be associated to side effects; therefore, clinicians should follow a stepladder approach starting with the least aggressive treatments to induce remission of inflammation. In this review, we reported the current evidence-based treatments for non-infectious uveitis in pediatric and adult patients with particular attention to the biologic response modifier treatment options. Important multicenter studies have demonstrated the efficacy of adalimumab, both in adults (VISUAL I, VISUAL II, VISUAL III) and in children (SYCAMORE, ADJUVITE), while for other agents data are still scarce.

Serum rheumatoid factors are autoantibodies of different isotypes directed against the Fc fraction of immunoglobulin G (IgG) and represent paradigmatic autoantibodies that have been largely used in clinical practice for decades. Traditionally IgG has been associated with rheumatoid arthritis and more recently included also in the classification criteria for Sjӧgren’s syndrome. Researchers have established that rheumatoid factors are positive in a variety of infectious, autoimmune, and neoplastic disorders, thus requiring a comprehensive evaluation of seropositive patients. Of note, hepatitis B and C viruses represent a crossroad that includes the high rheumatoid factor seroprevalence and chronic inflammatory disease, as well as progression to non-Hodgkin's lymphomas. Chronic antigen stimulation is the likely common ground of these processes and rheumatoid factors may represent mere bystanders or drivers of pathology. Mixed cryoglobulinemia and lymphoproliferative disease are prime examples of the deleterious effects of rheumatoid factor-B cell activity, possibly associated with hepatitis B and C. More importantly, they show a clear association in a physiological host response to infection, chronic inflammation, and the slide toward autoimmunity and malignancy. The association between hepatitis B and C infections and the appearance of serum rheumatoid factors is further supported by prevalence data, which support a coexistence of these markers in a significant proportion of cases, with viral infections being frequent causes of rheumatoid factors in patients without a rheumatic condition. We provide a comprehensive overview of the known connections between hepatitis B and C infections and rheumatoid factors.

Recurrent pericarditis is a state of repetitive inflammation of the pericardium with intervals of remission. The etiology of recurrent pericarditis is still largely unknown, yet most causes are presumed to be immune mediated. Genetic factors, including human leukocyte antigen (HLA) haplotypes, can be involved in dysregulation of the immune system and as a predisposition to several autoimmune conditions, including recurrent pericarditis. Several diseases are frequently associated with such manifestations. They include systemic lupus erythematosus, familial Mediterranean fever, and tumor necrosis factor receptor-associated periodic syndrome. However, idiopathic recurrent pericarditis remains the most frequently observed clinical condition and the conundrum of this disease still needs to be solved.

Background: Benign rolandic epilepsy or benign childhood epilepsy with centrotemporal spikes (BCECTS) is a common childhood epileptic syndrome. The syndrome resolves in adolescence, but 1–7% of patients have an atypical presentation, some of which require aggressive medical treatment. Early treatment may prevent complications and neurocognitive deterioration. Variants include Landau-Kleffner syndrome (LKS) and electrical status epilepticus during sleep (ESES).

Objectives: To determine data driven identification of risk factors and characterization of new subtypes of BCECTS based on anontology. To use data mining analysis and correlation between the identified groups and known clinical variants.

Methods: We conducted a retrospective cohort study comprised of 104 patients with a diagnosis of BCECTS and a minimum of 2 years of follow-up, between the years 2005 and 2017. The medical records were obtained from the epilepsy service unit of the pediatric neurology department at Dana–Dwek Hospital, Tel Aviv Sourasky Medical Center. We developed a BCECTS ontology and performed data preprocessing and analysis using the R Project for Statistical Computing (https://www.r-project.org/) and machine learning tools to identify risk factors and characterize subgroups.

Results: The ontology created a uniform and understandable infrastructure for research. With the ontology, a more precise characterization of clinical symptoms and EEG activity of BCECTS was possible. Risk factors for the development of severe atypical presentations were identified: electroencephalography (EEG) with spike wave (P < 0.05), EEG without evidence of left lateralization (P < 0.05), and EEG localization (centrotemporal, frontal, or frontotemporal) (P < 0.01).

Conclusions: Future use of the ontology infrastructure for expanding characterization for multicenter studies as well as future studies of the disease are needed. Identifying subgroups and adapting them to known clinical variants will enable identification of risk factors, improve prediction of disease progression, and facilitate adaptation of more accurate therapy. Early identification and frequent follow-up may have a significant impact on the prognosis of the atypical variants.

Background: In Israel, coronary heart disease mortality rates are significantly higher among the Arab population than the Jewish population. Dyslipidemia prevention should begin in childhood.

Objectives: To identify sociodemographic disparities in the preventive health measurement of lipid profile testing and lipoprotein levels among Israeli children and adolescents.

Methods: A cross-sectional analysis of 1.2 million children and adolescents insured by Clalit Health Services between 2007 and 2011 was conducted using sociodemographic data and serum lipid concentrations.

Results: Overall, 10.1% individuals had undergone lipid testing. Those with male sex (odds ratio [OR] = 0.813, 95% confidence interval [95%CI] 0.809–0.816), Arab ethnicity (OR = 0.952, 95%CI 0.941–0.963), and low socioeconomic status (SES) (OR = 0.740, 95%CI 0.728–0.752) were less likely to be tested. By 2010, differences among economic sectors narrowed and Arab children were more likely to be tested (OR = 1.039, 95%CI 1.035–1.044). Girls had higher total cholesterol, triglyceride, low-density lipoprotein-cholesterol, and non-high-density lipoprotein-cholesterol levels compared to boys (P < 0.001). Jewish children had higher cholesterol and low-density and high-density lipoprotein-cholesterol, as well as lower triglyceride levels than Arabs (P < 0.001). Children with low SES had lower cholesterol, low-density and high-density lipoprotein-cholesterol, and non-high-density lipoprotein-cholesterol levels (P < 0.001).

Conclusions: We found that boys, Arab children, and those with low SES were less likely to be tested. Over time there was a gradual reduction in these disparities. Publicly sponsored healthcare services can diminish disparities in the provision of preventive health among diverse socioeconomic groups that comprise the national population.

Background: Hypertrophy of the adenoids is common in children. However, the anatomical site makes the adenoids difficult to assess, and studies evaluating the subject are ambiguous, especially with regard to the use of X-ray as an evaluation tool.

Objectives: To compare medical history with clinical, radiological, and endoscopic evaluations of the adenoids and compare obstructed and non-obstructed children relative to the assessment methods.

Methods: A prospective comparative study was conducted with children who were suspected of having enlarged adenoids. All parents completed a medical history questionnaire and patients underwent clinical evaluation based on Nasal Obstruction Index (NOI) scores, radiological assessment based on the lateral neck X-ray adenoid–nasopharynx (A/N( ratio, and endoscopic evaluation based on anatomical relations. Spearman correlations were used for comparison between methods.

Results: We evaluated 36 patients, median age 5.33 years. Correlation measurements for clinical assessment and questionnaire (r = 0.582, P < 0.0001), questionnaire and endoscopy (r = 0.462, P = 0.005), and clinical assessment and nasal endoscopy (r = 0.621, P < 0.0001) were statistically significant. None of the parameters correlated with the radiological findings. A statistically significant difference was found between the obstructed and non-obstructed groups in both questionnaire (P = 0.004) and clinical assessment (P < 0.0001). However, no difference was found in X-ray measurements.

Conclusions: Lateral neck X-ray measurements were not correlated to symptoms, signs, or endoscopic findings. Therefore, medical professionals should use lateral neck radiography when considering adenoidectomy only on a highly selective basis.

Background: The sentinel lymph node (SLN) biopsy procedure is a well-known method for identifying solid tumors such as breast cancer, vulvar cancer, and melanoma. In endometrial and cervical cancer, SLN has recently gained acceptance.

Objectives: To evaluate the detection rate of SLN with an indocyanine green and near-infrared fluorescent imaging (ICG/NIR) integrated laparoscopic system in clinically uterine-confined endometrial or cervical cancer.

Methods: Patients with clinically early-stage endometrial or cervical cancer were included in this retrospective study. ICG was injected into the uterine cervix and an ICG/NIR integrated laparoscopic system was used during the surgeries. The National Comprehensive Cancer Network (NCCN) protocol was followed. SLN and/or suspicious lymph nodes were resected. Side-specific lymphadenectomy was performed when mapping was unsuccessful. Systematic lymphadenectomy was completed in patients with high-grade histology or deep myometrial invasion. Enhanced pathology using ultra-staging and immunohistochemistry were performed in all cases.

Results: We analyzed 46 eligible patients: 39 endometrial and 7 cervical cancers. Of these, 44 had at least one SLN (93.6%). In 41 patients (89%) we detected bilateral SLN, in 3 (7%) only unilateral, and in 2 (4%) none were detected. Seven patients presented with lymph node metastasis. All were detected by NCCN/SLN protocol. Of these cases, two were detected with only pathological ultra-staging.

Conclusions: SLN mapping in endometrial and cervical cancer can easily be performed with a high detection rate by integrating ICG/NIR into a conventional laparoscopic system. Precision medicine in patients evaluated by SLN biopsy changes the way patients with endometrial or cervical cancer are managed.

Background: The main acquired resistance mechanism to first- and second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR mutant non-small cell lung cancer (NSCLC) is the propagation of T790M clones, which can be detected in circulating tumor DNA (ctDNA).

Objectives: To analyze osimertinib outcomes according to T790M testing method.

Methods: The study comprised 33 consecutive patients with advanced EGFR mutant NSCLC who were diagnosed with a T790M mutation after progression on first- or second-generation EGFR TKIs and treated with osimertinib. The patients were divided into groups A (diagnosed by tumor testing) and B (by ctDNA testing). Osimertinib outcomes were compared between the groups.

Results: Objective response rate with osimertinib comprised 54% and 62% in groups A and B, respectively (P = 0.58). Median progression-free survival (PFS) with osimertinib was 8.9 months (95% confidence interval [95%CI] 1.8–17.5) and 9.1 months (95%Cl 5.3–12.6) in groups A and B, respectively (log-rank test 0.12, P = 0.73). Median overall survival (OS) was 13.8 months (95%CI 4.9–25.5) and 13.8 months (95%Cl 7.7–27.7) in groups A and B, respectively (log-rank test 0.09, P = 0.75). T790M testing technique did not affect PFS (hazard ratio [HR] 1.16, 95%CI 0.50–2.69, P = 0.73) or OS (HR = 1.16, 95%CI 0.45–3.01, P = 0.76). The proportion of patients diagnosed by ctDNA grew from 56% in 2015 to 67% in 2016–2017.

Conclusions: Our study provides a ctDNA validation for the purpose of T790M testing in EGFR mutant NSCLC.

Background: Hysterectomy is common in the management of symptomatic uterine prolapse. Vaginal wall repair is often necessary, for which vaginal mesh remains a popular option.

Objectives: To evaluate the risk of mesh erosion following mesh-augmented vaginal prolapse repair, with or without concomitant vaginal hysterectomy.

Methods: This retrospective cohort comprised 70 women who underwent vaginal mesh-augmented pelvic organ prolapse repair from 2007 to 2010. Of the participants, 36 (51.4%) had a vaginal hysterectomy concomitant to the anterior and/or posterior vaginal mesh repair (hysterectomy group) and 34 (48.6%) underwent mesh repair without vaginal hysterectomy (no hysterectomy group).

Results: There were no inter-group differences in age, parity, menopausal state, hormonal use, or presenting symptoms. Previous prolapse repair surgery was much more common in the no hysterectomy group (29.4% vs. 5.5%, P = 0.01). Eleven patients (32.3%) in the no hysterectomy group had previously undergone hysterectomy. Anterior mesh repair was performed in 77.7% and 67.6% of hysterectomy and no hysterectomy patients, respectively. Posterior mesh repair was performed in 27.7% and 44.1%, respectively. One patient in the hysterectomy group underwent immediate removal of mesh due to infection. Surgically treated mesh erosion (limited local excision) occurred in three patients (8.3%) in the hysterectomy group (3, 16, and 18 months following surgery) and in two patients (5.8%) in the no hysterectomy group at 6 months following surgery (P = 0.67).

Conclusions: Vaginal mesh-augmentation concomitant with vaginal hysterectomy for pelvic organ prolapse repair does not carry an increased risk of erosion.

Background: Cannabinoid hyperemesis syndrome (CHS) is under-recognized by clinicians. It is characterized by nausea, severe abdominal pain, and cyclical vomiting in the context of chronic cannabis use. Oral benzodiazepine is a proposed treatment for CHS. It decreases activation of Cannabinoid Type 1 Receptor (CB1) in the frontal cortex, has a sedative and hypnotic effect and reduces the anticipation of nausea and vomiting. These effects on the central nervous system (CNS) might explain its beneficial antiemetic effect for this syndrome.

Objectives: To increase the index of suspicion for CHS, a unique syndrome that requires a unique treatment with benzodiazepines and not antiemetics.

Methods: We describe a series of four patients with documented cannabis use, who were admitted to an internal medicine department of Meir Medical Center due to symptoms consistent with abdominal pain, nausea, and vomiting. They were initially treated with conventional antiemetics and proton pump inhibitors without response. Intensive investigations were conducted to exclude common and sometimes urgent gastrointestinal or CNS syndromes.

Results: After excluding urgent gastrointestinal and CNS origins for the vomiting, we suspected CHS. All four patients experienced similar symptoms and failure of conventional treatment with antiemetics and proton pump inhibitors. They experienced relief after administration of benzodiazepines.

Conclusions: A high index of suspicion for CHS allows for rapid, appropriate treatment with benzodiazepines, which in turn may lead to cessation of the debilitating symptoms caused by this syndrome.