The impact of co-morbidities on a 6-year survival after methanol mass poisoning outbreak: possible role of metabolic formaldehyde.

Context: The influence of co-morbid conditions on the outcome of acute methanol poisoning in mass poisoning outbreaks is not known.Objective: The objective of this is to study the impact of burden of co-morbidities, complications, and methanol-induced brain lesions on hospital, follow-up, and total mortality.Methods: All patients hospitalized with methanol poisoning during a mass poisoning outbreak were followed in a prospective cohort study until death or final follow-up after 6 years. The age-adjusted Charlson co-morbidity index (ACCI) score was calculated for each patient. A multivariate Cox regression model was used to calculate the adjusted hazards ratio (HR) for death. The survival was modeled using the Kaplan-Meier method.Results: Of 108 patients (mean age with SD 50.9 ± 2.6 years), 24 (54.4 ± 5.9 years) died during hospitalization (mean survival with SD 8 ± 4 days) and 84 (49.9 ± 3.0 years; p = .159) were discharged, including 27 with methanol-induced brain lesions. Of the discharged patients, 15 (56.3 ± 6.8 years) died during the follow-up (mean survival 37 ± 11 months) and 69 (48.5 ± 3.3 years; p = .044) survived. The hospital mortality was 22%, the follow-up mortality was 18%; the total mortality was 36%. Cardiac/respiratory arrest, acute respiratory failure, multiorgan failure syndrome, and arterial hypotension increased the HR for hospital and total (but not follow-up) mortality after adjustment for age, sex, and arterial pH (all p < .05). All patients who died in the hospital had at least one complication. A higher ACCI score was associated with greater total mortality (HR 1.22; 1.00-1.48 95% CI; p = .046). Of those who died, 35 (90%) had a moderate-to-high ACCI. The Kaplan-Meier curve demonstrated that patients with a high ACCI had greater follow-up mortality compared to ones with low (p = .027) or moderate (p = .020) scores. For the patients who died during follow-up, cancers of different localizations were responsible for 7/15 (47%) of the deaths.Conclusions: The character and number of complications affected hospital but not follow-up mortality, while the burden of co-morbidities affected follow-up mortality. Methanol-induced brain lesions did not affect follow-up mortality. Relatively high cancer mortality rate may be associated with acute exposure to metabolic formaldehyde produced by methanol oxidation.

Role of activation of lipid peroxidation in the mechanisms of acute methanol poisoning.

CONTEXT: The role of activation of lipid peroxidation in the mechanisms of acute methanol poisoning has not been studied. OBJECTIVE: We measured the concentrations of lipid peroxidation markers in acutely intoxicated patients with known serum concentrations of methanol and leukotrienes. METHODS: Blood serum samples were collected from 28 patients hospitalized with acute intoxication and from 36 survivors 2 years after discharge. In these samples, concentrations of 4-hydroxy-trans-2-hexenal (HHE), 4-hydroxynonenal (HNE), and malondialdehyde (MDA) were measured using the method of liquid chromatography-electrospray ionization-tandem mass spectrometry. RESULTS: The maximum acute serum concentrations of all three lipid oxidative damage markers were higher than the follow-up serum concentrations: HNE 71.7 ± 8.0 ng/mL versus 35.4 ± 2.3 ng/mL; p < .001; HHE 40.1 ± 6.7 ng/mL versus 17.7 ± 4.1 ng/mL; p < .001; MDA 80.0 ± 7.2 ng/mL versus 40.9 ± 1.9 ng/mL; p < .001. The survivors without methanol poisoning sequelae demonstrated higher acute serum concentrations of the markers than the patients with sequelae. A correlation between measured markers and serum leukotrienes was present: HNE correlated with LTC4 (r = 0.663), LTD4 (r = 0.608), LTE4 (r = 0.771), LTB4 (r = 0.717), HHE correlated with LTC4 (r = 0.713), LTD4 (r = 0.676), LTE4 (r = 0.819), LTB4 (r = 0.746), MDA correlated with LTC4 (r = 0.785), LTD4 (r = 0.735), LTE4 (r = 0.814), LTB4 (r = 0.674); all p < .001. Lipid peroxidation markers correlated with anion gap (r= -0.428, -0.388, -0.334; p = .026, .045, .080 for HNE, HHE, MDA, respectively). The follow-up serum concentrations of lipid oxidation markers measured in survivors with and without visual/neurological sequelae 2 years after discharge did not differ. CONCLUSION: Our results demonstrate that lipid peroxidation plays a significant role in the mechanisms of acute methanol poisoning. The acute concentrations of three measured biomarkers were elevated in comparison with the follow-up concentrations. Neuronal membrane lipid peroxidation seems to activate leukotriene-mediated inflammation as a part of the neuroprotective mechanisms. No cases of persistent elevation were registered among the survivors 2 years after discharge.

Leukotriene-mediated neuroinflammation, toxic brain damage, and neurodegeneration in acute methanol poisoning.

CONTEXT: The role of neuroinflammation in methanol-induced toxic brain damage has not been studied. OBJECTIVE: We studied acute concentrations and the dynamics of leukotrienes (LT) in serum in hospitalized patients with acute methanol poisoning and in survivors. METHODS: Series of acute cysteinyl-LT and LTB4 concentration measurements were performed in 28/101 hospitalized patients (mean observation time: 88 ± 20 h). In 36 survivors, control LT measurements were performed 2 years after discharge. RESULTS: The acute maximum (Cmax) LT concentrations were higher than concentrations in survivors: Cmax for LTC4 was 80.7 ± 5.6 versus 47.9 ± 4.5 pg/mL; for LTD4, 51.0 ± 6.6 versus 23.1 ± 2.1 pg/mL; for LTE4, 64.2 ± 6.0 versus 26.2 ± 3.9 pg/mL; for LTB4, 59.8 ± 6.2 versus 27.2 ± 1.4 pg/mL (all p < 0.001). The patients who survived had higher LT concentrations than those who died (all p < 0.01). Among survivors, patients with CNS sequelae had lower LTE4 and LTB4 than did those without sequelae (both p < 0.05). The LT concentrations increased at a rate of 0.4-0.5 pg/mL/h and peaked 4-5 days after admission. The patients with better outcomes had higher cys-LTs (all p < 0.01) and LTB4 (p < 0.05). More severely poisoned patients had lower acute LT concentrations than those with minor acidemia. The follow-up LT concentrations in survivors with and without CNS sequelae did not differ (all p > 0.05). The mean decrease in LT concentration was 30.9 ± 9.0 pg/mL for LTC4, 26.3 ± 8.6 pg/mL for LTD4, 37.3 ± 6.4 pg/mL for LTE4, and 32.0 ± 8.8 pg/mL for LTB4. CONCLUSIONS: Our findings suggest that leukotriene-mediated neuroinflammation may play an important role in the mechanisms of toxic brain damage in acute methanol poisoning in humans. Acute elevation of LT concentrations was moderate, transitory, and was not followed by chronic neuroinflammation in survivors.

Phenotypic features of CRB1-associated early-onset severe retinal dystrophy and the different molecular approaches to identifying the disease-causing variants.

PURPOSE: The aim of this study was to determine the molecular genetic basis of an early-onset severe retinal dystrophy in three unrelated consecutive patients of Czech origin and to describe their ocular phenotype. METHODS: DNA samples from two probands were analyzed using a genotyping microarray (Asper) followed by either target analysis of 43 genes implicated in retinal disorders by next generation sequencing or whole-exome sequencing, respectively. The third proband underwent conventional Sanger sequencing of CRB1 based on her ocular findings. RESULTS: All three probands harboured a known disease-causing mutation c.2843G>A; p.(Cys948Tyr) in the CRB1 gene. One individual was homozygous for this mutation, while in the other two probands c.2308G>A; p.(Gly770Ser) and c.3121A>G; p.(Met1041Val) were also identified in the heterozygous state, respectively. Both variants were novel and evaluated by in silico analysis as pathogenic. A false-negative result was observed in one of the two samples examined by the genotyping microarray. Disease onset in all patients was before the age of 7 years. Hypermetropic refractive error, bilateral nummular retinal pigmentation, retinal thickening and cystoid spaces in the macula were observed in two probands, aged 6 and 7 years. The third proband, aged 28 years, had bone spicule-like pigmentary changes associated with increased retinal nerve fiber layer. CONCLUSIONS: The first study reporting on the molecular genetic cause of non-syndromic early-onset severe retinal dystrophy in Czech patients identified one homozygous and two compound heterozygote probands with CRB1 mutations. Retina nerve fibre layer measurements should be considered an integral part of the clinical evaluation of retinal dystrophies. Detailed clinical examination and imaging can both direct molecular screening and help to confirm or refute disease causation of identified variants.

Successful Use of Hydroxocobalamin and Sodium Thiosulfate in Acute Cyanide Poisoning: A Case Report with Follow-up.

Hydroxocobalamin is an effective first-line antidote used mainly in monotherapy of cyanide poisonings, while the opinions are different on the effects of its combination with sodium thiosulfate. A 58-year-old male committed a suicide attempt by ingesting of 1200-1500 mg of potassium cyanide; he was unconscious for 1-1.5 min. after ingestion with the episode of generalized seizures. On admission to the ICU, the patient was acidotic (pH 7.28; HCO3 14.0 mmol/L, base excess -12.7 mmol/L, saturation O2 0.999) with high serum lactate (12.5 mmol/L). Hydroxocobalamin was administered 1.5 hr after ingestion in two subsequent intravenous infusions at a total dose of 7.5 g. The infusion was followed by continuous intravenous administration of 1 mL/hr/kg of 10% sodium thiosulfate at a total dose of 12 g. No complications and adverse reactions were registered. Serum lactate decreased to 0.6 mmol/L the same day, and arterial blood gases became normal (pH 7.49; HCO3 27.2 mmol/L, base excess 2.2 mmol/L, saturation O2 0.994). The follow-up examination 5 months later revealed no damage of basal ganglia and cerebellum on magnetic resonance imaging. The neurological examination revealed no pathological findings. On the ocular coherence tomography, the retinal nerve fibres layer was normal. In visual evoked potentials, there was a normal evoked complex on the left eye and minor decrease in amplitude on the right eye. Combination of hydroxocobalamin and sodium thiosulfate can have a positive effect on the survival without long-term neurological and visual sequelae in the cases of massive cyanide poisonings due to the possibility of a potentiation or synergism of hydroxocobalamin effects by sodium thiosulfate. This synergism can be explained by the different time-points of action of two antidotes: the initial and immediate effect of hydroxocobalamin, followed by the delayed, but more persistent effect of sodium thiosulfate.

Varicella zoster virus acute retinal necrosis following eye contusion: case report.

BACKGROUND: Acute retinal necrosis is a sight-threatening disease caused by the group of herpesviruses. The aim of this paper is to report a case of acute retinal necrosis following ocular trauma in a patient initially treated with vaso-active drugs and corticosteroids for presumed ocular ischemic syndrome. CASE PRESENTATION: A 51-years-old otherwise healthy man, who suffered from sudden visual loss in the left eye following contusion, was commenced on vaso-active drugs and systemic corticosteroids for suspected ocular ischemic syndrome with extensive swelling of the optic disc and macular edema. Subsequently, vision in the initially uninvolved right eye decreased. Polymerase chain reaction of vitreous samples and retinal biopsy confirmed varicella zoster virus. Despite intensive treatment with intravenous antiviral medication, the patient became completely blind in both eyes. CONCLUSION: Initial treatment of acute, unexplained visual decrease with systemic corticosteroids may lead to visual loss in patients with developing acute retinal necrosis. Ocular trauma could have induced and corticosteroid treatment promoted reactivation of a latent viral infection in our patient.