Israel Medical Association Journal

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive death of motor neurons leading to fatal paralysis. The causes of ALS remain unknown; however, evidence supports the presence of autoimmune mechanisms contributing to pathogenesis. Although several environmental factors have been proposed, the only established risk factors are older age, male gender, and a family history of ALS. To date, there are no diagnostic test for ALS, and clinicians rely on the combination of upper motor neuron and lower motor neuron signs in the same body region. The aim of this paper was to provide a comprehensive review of current clinical literature with special focus on the role of autoimmunity in ALS, differential diagnosis, and available therapeutic approaches. Current evidence suggests a contribution of the innate immune system in ALS, with a role of microglial cell activation at the sites of neurodegeneration. The median time from symptom onset to diagnosis of ALS is 14 months, and this time estimate is mainly based on specific clinical signs and exclusion of ALS-like conditions. Several therapeutic approaches have been proposed, including immunosuppressive drugs, to reduce disease progression. Riluzole has been established as the only, although modestly effective, disease modifying therapy, extending mean patient survival by 3to 6 months. Recent advances in understanding the pathophysiology mechanisms of ALS encourage realistic hope for new treatment approaches. To date, the cornerstones of the management of patients with ALS are focused on symptom control, maintaining quality of life and improving survival.

Platelets have the ability to influence the immune system and the inflammatory process and may be strongly involved in the whole pathogenic process of chronic inflammatory joint diseases, such as rheumatoid arthritis. They may play a significant role even before the clinical onset of the disease, contributing to the loss of tolerance of the immune system and the induction of autoimmunity. Subsequently, they can interact with the most important cellular players involved in autoimmunity and inflammation, namely innate immunity cells and T cells and eventually contribute to the building of inflammation in the synovium, thus inducing the activation, migration, and proliferation of fibroblasts that eventually lead to joint damage. Due to their peculiar features, studying the behavior of platelets is a challenging task; however, platelets may prove to be valuable therapeutic targets in the future.

Inflammation is the basic mechanism leading to many pathological processes, including degenerative diseases, atherosclerosis, and cancer. We found an interesting link connecting rheumatoid arthritis and atherosclerosis that may explain the high cardiovascular event rate among patients with rheumatoid arthritis, but also may lead to a new way of thinking and a better understanding of atherosclerosis. Rheumatoid arthritis could serve as a model of accelerated atherosclerosis. Understanding the basic mechanisms of rheumatoid arthritis may solve some of the complexity of atherosclerosis.

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: Malignancy is a known risk factor for venous thromboembolism; however, the association with arterial thromboembolic events remains unclear.

Objectives: To examine the association between non-ST-elevation myocardial infarction (NSTEMI) and non-significant coronary artery disease (CAD) and the presence of new or occult malignancy.

Methods: An observational cohort, single-center study was performed 2010–2015. Adult patients with NSTEMI, who underwent coronary angiography and had no significant coronary lesion, were included. Using propensity score matching, we created a 2:1 matched control group of adults with NSTEMI, and significant coronary artery disease. Risk factors for new or occult malignancy were assessed using multivariate backward stepwise logistic regression analysis. The primary outcome was new or occult malignancy, defined as any malignancy diagnosed in the 3 months prior and 6 months following the myocardial infarction (MI).

Results: During the study period, 174 patients who presented with MI with non-obstructive coronary arteries were identified. The matched control group included 348 patients. There was no significant difference in the group demographics, past medical history, or clinical presentation. The incidence of new or occult malignancy in the study group was significantly higher (7/174, 4% vs. 3/348, 0.9%, P = 0.019). NSTEMI with non-significant CAD was an independent risk factor for occult malignancy (odds ratio [OR] 4.6, 95% confidence interval [95%CI] 1.1–18.7). Other risk factors included active smoking (OR 11.2, 95%CI 2.5–49.1) and age (OR 1.1, 95%CI 1.03–1.17).

Conclusions: NSTEMI with non-significant CAD may be a presenting or early marker of malignancy and warrants further investigation.

Background: The MitraClip procedure is becoming an acceptable alternative for high-risk patients with mitral regurgitation (MR) due to functional (FMR) or degenerative (DMR) disease and suitable mitral anatomy.

Objectives: To evaluate the results of MitraClip at our institute in carefully selected patients.

Methods: We conducted a retrospective analysis of medical records and echocardiography data from January 2012 to December 2017.

Results: A total of 39 MitraClip procedures in 37 patients (aged 75 ± 12 years, 9 women) was performed. Twenty-four patients presented with FMR, 12 with DMR, and 1 with combined pathology. One-day post-procedure MR was moderate to low in 86.1% of patients, with immediate device success in 88.8%. MR at 1 year was moderate to low in 79% at 1 year. Survival at 1 year was 86% and at 2 years 69.4%. Peri-procedural (< 1 week) death and MitraClip failure occurred in one and three patients, respectively. New York Heart Association score improved to class 1 or 2 in 37% of patients at 1 year vs. one patient at baseline. Post-procedural systolic pulmonary pressure was reduced from 53 (range 48–65) to 43 (range 36–52) mmHg at 1 month with a subsequent plateau at follow-up, to 41 (34–57) mmHg at 6 months, and to 47 (38–50) at 12 months.

Conclusions: MitraClip in severe MR resulted in modest improvement in functional status and pulmonary pressure with a small risk of immediate procedural complications. Outcomes are encouraging considering the natural course of MR and the risks of surgical intervention.

Background: Access-site bleeding is a common complication of transfemoral transcatheter aortic valve implantation (TAVI). Percutaneous stent-graft implantation within the femoral artery may achieve hemostasis and avert the need for more invasive surgical vascular repair; however, failure to advance a guidewire antegradely via the injured vessel may preclude stent delivery. While retrograde stent-graft delivery from the distal vasculature may potentially enable percutaneous control of bleeding, this approach has not been reported.

Objectives: To assess the feasibility of a retrograde approach for stent-graft implantation in the treatment of access-site bleeding following transfemoral TAVI.

Methods: A prospective TAVI registry was analyzed. Of 349 patients who underwent TAVI, transfemoral access was used in 332 (95%). Access-site injury requiring stent-graft implantation occurred in 56 (17%). In four patients (7%), antegrade wiring across the site of vascular injury was not possible and a retrograde approach for stent delivery was used.

Results: Distal vascular access was achieved via the superficial femoral or profunda artery. Retrograde advancement of a polymer-coated 0.035” wire to the abdominal aorta, followed by stent-graft delivery to the common femoral artery, achieved hemostasis in all cases. During a median (interquartile range) follow-up period of 198 (618) days (range 46–2455) there were no deaths and no patient required additional vascular interventions.

Conclusions: A retrograde approach for stent-graft delivery is feasible and allows percutaneous treatment of a common femoral artery injury following TAVI in patients who are not suitable for the conventional antegrade approach.

Background: Methotrexate is the most frequently administered first-line treatment for rheumatoid arthritis (RA). The disease-modifying effects of methotrexate are mainly associated with enhanced release of free adenosine. The downstream anti-inflammatory effects of adenosine are mediated via its binding to adenosine receptor 2A (ADORA2A) and 3 (ADORA3). Many clinically important single nucleotide polymorphisms (SNPs) were reported in ADORA2A and ADORA3 genes.

Objectives: To investigate whether tagging ADORA2A and ADORA3 polymorphisms influences methotrexate treatment in RA.

Methods: In total, 212 RA patients treated with methotrexate were genotyped for tagging ADORA2A (rs2298383, rs8141793, rs2236624, rs5751876, rs35320474, and rs17004921) and ADORA3 SNPs (rs2298191, rs1544223, rs78594984, rs35511654, rs2229155, rs3393, and rs3394).

Results: RA patients who carried ADORA3 rs35511654 G allele showed a tendency toward better response to methotrexate treatment (P = 0.054). Carriers of ADORA2A polymorphic allele rs2298383 (P = 0.011), rs2236624 (P = 0.027), rs5751876 (P = 0.018), and rs35320474 (P = 0.026) were less likely to experience methotrexate induced adverse events. All associations remained significant after adjustment for clinical factors. The effects of these polymorphisms were also significant in haplotype analyses.

Conclusions: Polymorphisms in the ADORA2A gene may influence methotrexate treatment response and may be considered as a potential biomarker for methotrexate treatment in rheumatoid arthritis.

Angiogenesis is the outgrowth of new blood vessels from existing ones and is an early occurrence in inflamed joint tissue. It is governed by a tightly controlled balance of pro- and anti-angiogenic stimuli, which promote or inhibit generation and proliferation of new endothelial cells, vascular morphogenesis, and vessel remodeling. At the beginning, capillary formation is crucial in maintaining the supply of various nutrients as well as oxygen to the inflamed tissue. Local and systemic expression of angiogenic factors may indicate a constant remodeling of synovial vasculature. Redox signaling is closely related to angiogenesis and can alter angiogenic responses of synovial cells. In this review we discuss key issues about the endothelial pathology in inflammatory arthritis followed by a review of angiogenic processes and main angiogenic mediators. We discuss the hypoxia-vascular endothelial growth factor (VEGF)-Ang/Tie2 system and its related therapeutic implications in detail with further review of various mediator protein targets and intracellular regulatory pathway targets with their current and potential future role in preclinical or clinical setting whilst ameliorating inflammation.

Background: Multidisciplinary biopsychosocial rehabilitation for patients presenting with rheumatic diseases has been shown to produce better results in a warm climate. Dead Sea Climatotherapy (DSC) has been successfully used for decades to treat many patients with rheumatic diseases.

Objectives: To evaluate the short-term improvement of Norwegian patients who presented with chronic pain following a multidisciplinary biopsychosocial approach to treatment combined with DSC. Both objective and subjective clinical parameters were evaluated.

Methods: This retrospective study included a statistical analysis of 938 patients presenting with rheumatoid arthritis and ankylosing spondylitis (n=105), osteoarthritis (n=342), fibromyalgia (n=374), and other orthopedic conditions (n=117). Clinical assessments were conducted before and after a 3 week treatment program at the Dead Sea.

Results: Six parameters improved significantly in the rheumatoid arthritis and ankylosing spondylitis group as well as in the osteoarthritis group. Five parameters in the fibromyalgia group improved, while two improved in the orthopedic conditions group. Overall, major significant changes occurred in the pain self-assessment, joint motility, and daily activities scores.

Conclusions: A 3-week multidisciplinary biopsychosocial program combined with DSC induced positive changes in the clinical parameters of Norwegian patients presenting with chronic musculoskeletal pain.

Background: The number of patients undergoing shoulder arthroplasty is increasing yearly.

Objectives: To evaluate the results of a consecutive series of patients who underwent shoulder replacement for a variety of indications in a single medical center in Israel.

Methods: All shoulder arthroplasties performed in our institution between 2006 and 2015 were retrospectively reviewed. The functional outcomes and satisfaction of 180 shoulder arthroplasties were evaluated for objective and subjective parameters using the American Shoulder and Elbow Surgeons Shoulder Score (ASES), the Disabilities of the Arm, Shoulder and Hand (DASH) outcome measure, and the Short Form Health Survey (SF-12).

Results: The indications for surgery were osteoarthritis (n=35), rotator cuff arthropathy (n=32), fractures (n=99), and other reasons (n=14). The mean follow-up was 52 months. The scores improved markedly among the patients who underwent surgery later in the study period. The mean DASH score before 2012 was 48.8 and improved to 37.2 after 2013. The respective ASES also improved from 54.2 to 68.6. The use of hemiarthroplasty decreased from 85% to 33% as of 2013, while the use of total shoulder arthroplasty increased.

Conclusions: Shoulder arthroplasty represents an effective treatment modality with satisfactory functional outcomes. Our current study demonstrates a shift from hemiarthroplasty to total shoulder arthroplasty, with the number of procedures increasing yearly. Surgeon experience and the expanding volume of operations had a direct positive effect on the functional outcomes of shoulder arthroplasties.

Background: Horse riding has become increasingly popular in recent years and is a common activity among children. As a result, pediatric horse-related injuries are frequently encountered in emergency departments.

Objectives: To examine the characteristics of horse-related injuries in the pediatric population.

Methods: We collected and analyzed the data on all pediatric horse-related injuries presented to a tertiary hospital, level one trauma center, during the years 2006–2016.

Results: A total of 53 children with horse-related injuries were documented. Forty-two patients were male (79%) and their mean age was 11.13 ± 4.72 years. The most common mechanism of injury was falling off a horse (31 patients, 58%) and the most common type of injury was skeletal (32 patients, 60%). Head injuries occurred in 16 patients (30%) and facial injuries in 12 (23%). The mean Injury Severity Score (ISS) was 10.5 ± 6.32, and 15 patients (28%) had severe trauma (ISS > 15). Twenty-nine patients (55%) required trauma team intervention, 12 (23%) were admitted to the intensive care unit, and 24 (45%) required surgery. The mean length of hospitalization was 4.3 ± 3.14 days.

Conclusions: Our study suggests that horse-related trauma may involve serious injuries and it exhibits typical injury patterns. Young boys are at highest risk. The potential severity of these injuries merits a thorough evaluation. We suggest that these injuries be triaged appropriately, preferably to a medical facility with proper trauma capabilities.

Background: The Israel Poison Information Center (IPIC), Rambam Health Care Campus, provides 24-hour telephone consultations on clinical toxicology and drug and reproductive toxicology. It participates in research, teaching and regulatory activities, and provides laboratory services. In 2014, nurse specialists in poison information joined the IPIC.

Objectives: To report the epidemiology of poison exposures in Israel.

Methods: We present computerized queries and a descriptive analysis of the medical records database of the IPIC for 2017.

Results: A total of 39,928 poison exposure cases were recorded, reflecting increases of 226.3% and 26.7% compared with 1995 and 2012, respectively. Children < 6 years of age were involved in 47.0% of cases; 80.4% of calls were made by the public and 17.8% by physicians; 74.2% of exposures were unintentional and 7.3% intentional. Pharmaceuticals were involved in 51.4% of cases, chemicals in 36.9%, bites and stings in 2.2%, and plants and mushrooms in 1.5%. Substances most frequently involved were analgesics, cleaning products, and antimicrobials. Clinical severity was moderate/major in 3.3%, mainly due to insecticides, drugs of abuse, and corrosives. Three fatalities were recorded (due to colchicine, organophosphates, and volatile substance inhalant abuse).

Conclusions: Poison exposures and poisonings have markedly increased in Israel, contributing substantially to morbidity. The IPIC prevented unnecessary referrals to emergency departments. Its database is a valuable national resource for collecting and monitoring poisoning exposure cases. It can be used as a real-time surveillance system for the benefit of public health. It is recommended that reporting to the IPIC become mandatory, and its activities adequately supported by national resources.