Serotonin syndrome: history and risk

Summary— This review focuses on the history of investigations into the behavioural reaction resulting from excess stimulation of postsynaptic 5-hydroxytryptamine receptors and the relative risk of this occurring with different combinations of drugs. Other aspects, particularly treatment with 5-hydroxytryptamine receptor antagonists, are reviewed in a recent separate paper [44]. The first human case was in 1955 and animal work had defined the characteristic features by 1958, and established they were lessened by chlorpromazine. Substantial evidence of a 'dose-effect' relationship existed by 1984. The relative risk with different drug combinations is assessed from available evidence and argued to be strongly associated with the degree of elevation of 5-hydroxytryptamine, which is greatest following combinations of irreversible inhibitors of monoamine oxidase A and B with potent serotonin reuptake inhibitors. The various serotonergic drugs that may be implicated in serotonin syndrome are tabulated and discussed in relation to the relative risk. It is suggested that the proposed 'diagnostic criteria' for serotonin syndrome are inappropriate since there is a continuous spectrum from side effects to toxicity. The term 'serotonin syndrome' may encourage the presumption that it is an idiosyncratic response, as neuroleptic malignant syndrome is usually considered to be. The terms 'toxic serotomimetic reaction' or 'toxic serotonin syndrome' may be preferable alternatives. The differences between serotonin syndrome and neuroleptic malignant syndrome are highlighted with examples from difficult or questionable cases in the recent literature. It is proposed that more systematic national collection of toxicity data is essential in order to quantify the relative risk of serotonin syndrome with various combinations of serotonergic drugs.     

Myriad manifestations of Williams syndrome

4 months male child presented with failure to thrive. On general examination child had normal O2 saturation with characterstic elfin facies. Further evaluation of the patient showed major manifestations of Williams syndrome in form of supravalvar aortic stenosis, branched pulmonary artery stenosis along with cardiomyopathy. Although the entity is known, this article shows comprehensive diagnostic workup with the aid of multimodality imaging techniques. The genetic diagnosis of Williams syndrome was confirmed using fluroscent in situ hybridisation techniques (FISH). In this patient most of the manifestations of elastin vasculopathy were noted in the form of involvement of ascending aorta, pulmonary arteries and myocardium. We also want to emphasis the importance of echocardiography in newborn patients with dysmorphic facies as Williams syndrome can be easily missed in neonatal period.A 4 month old male child presented with symptoms of heart failure and poor weight gain. On examination, O₂ saturation in both limbs was 99% and there was no significant blood pressure difference in all four limbs. He had a characterstic ‘elfin facies’ with a sunken nasal bridge, a long philtrum, wide mouth, prominent lower lip, small chin and low set ears (Fig. 1). 2D echocardiography showed situs solitus, concentric left ventricular hypertrophy with mild narrowing in the supravalvular region (Fig. 2) with systolic gradients of 26 mm Hg across the segment (Fig. 3) (Online Video 1). The right pulmonary artery (RPA) after its origin showed significant short segment stenosis with peak systolic gradients of 32 mmHg. The left pulmonary artery (LPA) after its origin showed mild narrowing (Figs. 4 and 5) (Online Video 2). Cardiac CT demonstrated supravalvular aortic stenosis (SVAS) with hour glass appearance of the aorta (Figs. 6 and 7) with bilateral pulmonary artery stenosis (PAS) involving RPA more than LPA (Figs. 8 and 9). Fluorescent in-situ hybridization (FISH) studies (Fig. 10) showed heterozygous deletion of elastin gene (Chromosome 7q11.23) and confirmed the diagnosis of Williams syndrome (WS).Open in a separate windowFig. 1Characterstic elfin facies.Open in a separate windowFig. 22D echocardiography showing mild narrowing in the supravalvular region.Open in a separate windowFig. 3Doppler showing gradients of 26 mm Hg across narrowed supravalvular region.Open in a separate windowFig. 42D echocardiography with color Doppler showing bilateral PAS.Open in a separate windowFig. 5Doppler investigation showing peak systolic gradients of 32 mmHg across the narrowed segment of RPA.Open in a separate windowFig. 6Cardiac CT with 3D reconstruction showing supravalvular aortic stenosis (SVAS).Open in a separate windowFig. 7Cardiac CT (Coronal section) showing SVAS.Open in a separate windowFig. 8Cardiac CT (Transverse section) showing bilateral PAS.Open in a separate windowFig. 9Cardiac CT with 3D reconstruction showing bilateral pulmonary artery stenosis (PAS) involving RPA more than LPA.Open in a separate windowFig. 10Fluorescent in-situ hybridization studies showing deletion of elastin gene (Chromosome 7q11.23).Supplementary data related to this article can be found online at http://dx.doi.org/10.1016/j.ihj.2015.02.026.The following are the Supplementary data related to this article:Video 1: Subcostal view showing turbulence in supravalvar region of aorta and the branched pulmonary arteries.Click here to view.^{(1.3M, mp4)}Video 2: High parasternal view showing confluent pulmonary arteries with turbulence across the branched pulmonary arteries.Click here to view.^{(853K, mp4)}WS is a genetic disorder occurring with a frequency of 1 in 20,000–50,000 live births. Manifestations of WS include congenital heart disease, hypertension, dysmorphic facial features, infantile hypercalcaemia and mental retardation. Apart from supravalvular AS and branched PA stenosis other cardiac abnormalities observed are bicuspid aortic valve, mitral valve regurgitation, coarctation of the aorta, ventricular or atrial septal defects. In neonates, cardiovascular symptoms were evident in 47% of WS children.1 PA stenosis often tends to regress spontaneously and SVAS tends to progress with time. In this patient most of the manifestations of elastin vasculopathy were noted in the form of involvement of ascending aorta and pulmonary arteries. The concentric left ventricular hypertrophy observed in our patient may be an expression of hypertrophic cardiomyopathy which is known to be associated with WS.1 In neonatal period all newborn patients with dysmorphic facies should be evaluated with echocardiography so that the cardiac abnormalities are not missed.     

Platelet-derived growth factor concentrations in platelet-poor plasma and urine from patients with myeloproliferative disorders

Our enzyme-linked immunosorbent assay (ELISA) for measuring human platelet-derived growth factor (PDGF) detects nanogram quantities (ranging from 0.007 to 16 ng/100 microL) in purified PDGF standards. This assay is sensitive enough for studying plasma and urine. The range in normal volunteers was 0.6 to 2.3 micrograms/L for platelet-poor plasma and 1.4 to 3.3 micrograms/L for urine. We determined PDGF levels in the circulation (outside platelets) in patients with myeloproliferative diseases. Platelet-poor plasma and urine PDGF were significantly elevated in patients with myelofibrosis (6.2 +/- 2.0 micrograms/L for plasma; 7.8 +/- 2.4 micrograms/L for urine) and essential thrombocythemia (5.5 +/- 1.5 micrograms/L for plasma; 11.4 +/- 2.2 micrograms/L for urine), but not in patients with chronic myelogenous leukemia (2.1 +/- 0.4 micrograms/L for plasma; 2.8 +/- 1.2 micrograms/L for urine). Polycythemia vera produced an intermediate pattern: although plasma PDGF was within the normal range (2.1 +/- 0.2 micrograms/L), urine levels were increased (3.7 +/- 0.6 micrograms/L). These results show that PDGF is increased in the circulation in some but not all myeloproliferative diseases, and suggest that this is due to abnormal in vivo release from either megakaryocytes in the bone marrow or circulating platelets.     

Human platelet cytoskeletons: specific content of glycolipids and phospholipids

The lipid composition of platelet cytoskeletons was analyzed. Triton X- 100 (0.5%) was used to prepare cytoskeletons from thrombin-treated platelets. The lipid/protein ratio of platelet cytoskeletons was 0.260 and the phospholipid/protein ratio was 0.177, which were comparable to the ratios present in platelets. However, there was a selective enrichment of platelet lipids in platelet cytoskeletons. Only 2 of the 5 major platelet phospholipids were detected. About 14% platelet sphingomyelin and 2% platelet phosphatidylcholine were present in platelet cytoskeletons. Only 1 of the 4 platelet neutral glycolipids, trihexosyl ceramide, was detected and was about 7% of that in intact platelets. Two percent of platelet hematoside, the predominant ganglioside in platelets, was found in cytoskeletons. Six percent of platelet cholesterol was present in platelet cytoskeletons, while no other neutral lipid could be detected. The study demonstrates that the lipid/protein ratio of platelet cytoskeletons is similar to that in platelets, but the composition of cytoskeleton lipids is specific and distinctly different from that in platelets. The selective glycolipid and phospholipid composition of cytoskeletons may be important for cytoskeleton and platelet function.     

Immunolocalization of inducible nitric oxide synthase in synovium and cartilage in rheumatoid arthritis and osteoarthritis

Nitric oxide has been implicated as a mediator of inflammatory arthritis, and recent work has shown that pro-inflammatory cytokines stimulate NO production in vitro by activation of the inducible nitric oxide synthase (iNOS) pathway. In order to identify the cellular sources of NO production within the joint, we have used immunohistochemical techniques to study the distribution of iNOS in synovium and cartilage from normal and diseased joints. iNOS was most strongly expressed in the synovial lining layer, subsynovium, vascular smooth muscle and chondrocytes from patients with rheumatoid arthritis (RA). Analysis of serial sections, coupled with double immunofluorescent staining, showed that the CD68+ macrophages in the synovial lining layer and, to a lesser extent, fibroblasts were the predominant source of iNOS within synovium, whereas T cells, B cells and neutrophils were negative. A similar pattern of iNOS staining was seen in osteoarthritis, but fewer cells were iNOS positive and the intensity of staining, particularly in cartilage, was much weaker than in RA. In contrast, no evidence of iNOS was detected in non- inflammatory synovium or in cartilage derived from normal joints (fractured neck of femur). In conclusion, these data support the hypothesis that synovium and cartilage are important sources of increased NO production in patients with inflammatory arthritis. Localization of iNOS at these sites within the inflamed joint raises the possibility that increased local production of NO may contribute to the pathogenesis of inflammatory arthritis by increasing synovial blood flow and by modulating cellular function within synovium and articular cartilage.