Imbalance of the renin-angiotensin system may contribute to inflammation and fibrosis in IBD: a novel therapeutic target?

OBJECTIVE: We evaluated the influence of the renin-angiotensin system (RAS) on intestinal inflammation and fibrosis. DESIGN: Cultured human colonic myofibroblast proliferation and collagen secretion were assessed following treatment with angiotensin (Ang) II and Ang (1-7), their receptor antagonists candesartan and A779, and the ACE inhibitor captopril. Circulating and intestinal RAS components were evaluated in patients with and without IBD. Disease outcomes in patients with IBD treated with ACE inhibitors and angiotensin receptor blockers (ARBs) were assessed in retrospective studies. RESULTS: Human colonic myofibroblast proliferation was reduced by Ang (1-7) in a dose-dependent manner (p<0.05). Ang II marginally but not significantly increased proliferation, an effect reversed by candesartan (p<0.001). Colonic myofibroblast collagen secretion was reduced by Ang (1-7) (p<0.05) and captopril (p<0.001), and was increased by Ang II (p<0.001). Patients with IBD had higher circulating renin (mean 25.4 vs 18.6 mIU/L, p=0.026) and ACE2:ACE ratio (mean 0.92 vs 0.69, p=0.015) than controls without IBD. RAS gene transcripts and peptides were identified in healthy and diseased bowels. Colonic mucosal Masson's trichrome staining correlated with Ang II (r=0.346, p=0.010) and inversely with ACE2 activity (r=-0.373, p=0.006). Patients with IBD who required surgery (1/37 vs 12/75, p=0.034) and hospitalisation (0/34 vs 8/68, p=0.049) over 2 years were less often treated with ACE inhibitors and ARBs than patients not requiring surgery or hospitalisation. CONCLUSIONS: The RAS mediates fibrosis in human cell cultures, is expressed in the intestine and perturbed in intestinal inflammation, and agents targeting this system are associated with improved disease outcomes.

EEG changes in patients on antipsychotic therapy: A systematic review.

OBJECTIVES: The objective of the study was to characterize the electroencephalogram (EEG) changes associated with different antipsychotic medications based on the evidence from the literature. METHODS: A systematic search of the databases Medline, PsycINFO, and PubMed was conducted. The Preferred Items Reporting for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed in the construction of this systematic review. Primary research articles that reported descriptive EEG results, included comparisons of subjects with and without antipsychotic therapy, and excluded patients with epilepsy were included in the analysis. The outcome was the presence of epileptiform discharges or slowing on EEG. We analyzed pooled data, where possible, from studies with a similar intervention and methodology. RESULTS: Fourteen articles reporting on a total of 665 patients were reviewed. Among the publications, clozapine was the drug most consistently accompanied by EEG slowing and epileptiform discharges, with an odds ratio of 16.9 (95% confidence intervals (CI): 5.4 to 53.2) and 6.2 (95% CI: 3.4 to 11.3), respectively in the analysis of pooled data. Only one study reported a significant increase in epileptiform discharges with phenothiazine antipsychotic therapy as a group, but the impact of individual drugs was not analyzed separately. CONCLUSIONS: This systematic review suggests that, among antipsychotics, clozapine most frequently induces EEG slowing and epileptiform discharges. There remains limited data with respect to other individual antipsychotic agents and covariates including drug dose, plasma levels, dose adjustments, and treatment duration that influence EEG changes.

Challenges in the first seizure clinic for adult patients with epilepsy.

AIMS: (1) To delineate the challenges in seizure diagnosis in the first seizure clinic setting for adult patients of a teaching hospital, and (2) quantify the diagnostic accuracy of the referral source and the yield of routine investigations, including blood tests, EEGs, and neuroimaging. METHODS: We retrospectively reviewed medical records of patients referred by the emergency department to the adult first seizure clinic and seen by the same epilepsy specialist between June 2007 and June 2011. The diagnostic accuracy in the emergency department was calculated by comparing with the final diagnosis made by an epilepsy specialist. RESULTS: In total, 219 patients were referred to the first seizure clinic. Median age was 45 and 60% of patients were male. From the cohort, 38 (17%) patients presented with seizure mimickers; the most common were reflex syncope (74%) and psychogenic non-epileptic seizures (16%). From the remaining 181 patients presenting with seizures, only 110 (61%) of these patients were diagnosed with true first seizures, and 71 (39%) patients had evidence of previous seizures. Nineteen (17%) of true first-ever seizures were provoked. The most frequent cause of provoked seizures was alcohol and illicit drugs (65%). In the emergency department, sensitivity and specificity in seizure diagnosis were 0.74 and 0.32, respectively. In our true first seizure patients, the EEG demonstrated epileptiform discharges in 22 (21%) patients. In the same cohort, computed tomography and magnetic resonance neuroimaging conferred 16% and 20% probability of finding a potentially epileptogenic structural abnormality, respectively. The most common epileptogenic abnormality found on magnetic resonance neuroimaging was cortical infarct. CONCLUSIONS: The diagnosis and management of first seizure remains challenging due to the variety of seizure mimickers and low yield of investigations. Our data highlight the potential pitfalls and practical challenges in this process, as well as the need for these patients to be assessed in dedicated first seizure clinics.

Semiologic, electroencephalographic and electrocardiographic correlates of seizure-like manifestations caused by cardiac asystole.

PURPOSE: Cardiac asystole is known to cause clinical manifestations mimicking seizures. The recognition of this uncommon phenomenon is important to expedite appropriate clinical intervention and avoid unnecessary morbidity as well as potential mortality. METHODS: We retrospectively reviewed video-electroencephalographic (EEG) records from January 2008 to December 2013 for relevant cases. RESULTS: We identified four patients who experienced nine events of asystole accompanied by seizure-like activity captured on video-EEG. None had evidence of epilepsy on video-EEG. Semiological features of captured clinical events included aura, automatisms, generalized tonic activity and focal as well as generalized myoclonus. No patient had generalized tonic-clonic seizures. A peculiar rapid breathing pattern was seen preceding the onset of asystole. General pallor was observed during asystole, followed by flushing on recovery. Seizure-like semiology was observed in three stages; pre-asystole, during asystole and after resumption of cardiac rhythm. The EEG demonstrated generalized slowing followed by generalized suppression during asystole and generalized slowing again on resumption of sinus rhythm ("slow-flat-slow" pattern). All patients had dual-chamber pacemakers implanted. On follow-up, they have remained symptom-free without antiepileptic medications. CONCLUSIONS: Cardiac asystole can be associated with features closely mimicking seizures. Recurrent episodes of cardiac asystole can be stereotypical in a given patient. There are some diagnostic clues in semiology.