Study objective Methanol poisoning outbreaks are a global public health issue, with delayed treatment causing poor outcomes. Out-of-hospital ethanol administration may improve outcome, but the ...difficulty of conducting research in outbreaks has meant that its effects have never been assessed. We study the effect of out-of-hospital ethanol in patients treated during a methanol outbreak in the Czech Republic between 2012 and 2014. Methods This was an observational case-series study of 100 hospitalized patients with confirmed methanol poisoning. Out-of-hospital ethanol as a “first aid antidote” was administered by paramedic or medical staff before the confirmation of diagnosis to 30 patients; 70 patients did not receive out-of-hospital ethanol from the staff (12 patients self-administered ethanol shortly before presentation). Results The state of consciousness at first contact with paramedic or medical staff, delay to admission, and serum methanol concentration were similar among groups. The median serum ethanol level on admission in the patients with out-of-hospital administration by paramedic or medical staff was 84.3 mg/dL (interquartile range 32.7 to 129.5 mg/dL). No patients with positive serum ethanol level on admission died compared with 21 with negative serum ethanol level (0% versus 36.2%). Patients receiving out-of-hospital ethanol survived without visual and central nervous system sequelae more often than those not receiving it (90.5% versus 19.0%). A positive association was present between out-of-hospital ethanol administration by paramedic or medical staff, serum ethanol concentration on admission, and both total survival and survival without sequelae of poisoning. Conclusion We found a positive association between out-of-hospital ethanol administration and improved clinical outcome. During mass methanol outbreaks, conscious adults with suspected poisoning should be considered for administration of out-of-hospital ethanol to reduce morbidity and mortality.
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.
We report the results of the visual evoked potentials (VEP) examination in patients after severe poisoning by methanol.
The group of 47 patients (38 males and 9 females) was assembled out of persons ...who survived an outbreak of poisoning by the methanol adulterated alcohol beverages, which happened in the Czech Republic in 2012-2013. The visual evoked potentials examination was performed using monocular checkerboard pattern-reversal stimulation. Two criteria of abnormality were chosen: missing evoked response, and wave P1 latency > 117 ms. Non-parametric statistical methods (median, range, and the median test) were used to analyze factors influencing the VEP abnormality.
The visual evoked potential was abnormal in 20 patients (43%), 5 of them had normal visual acuity on the Snellen chart. The VEP abnormality did not correlate significantly with initial serum concentrations of methanol, formic acid or lactate; however, it showed statistically significant inverse relation to the initial serum pH: the subgroup with the abnormal VEP had significantly lower median pH in comparison with the subgroup with the normal VEP (7.16 vs. 7.34, p = 0.04). The abnormality was not related to chronic alcohol abuse.
The visual evoked potentials examination appeared sensitive enough to detected even subclinical impairment of the optic system. Metabolic acidosis is likely to be the key factor related to the development of visual damage induced by methanol. The examination performed with a delay of 1-9 months after the poisoning documented the situation relatively early after the event. It is considered as a baseline for the planned long-term follow-up of the patients, which will make it possible to assess the dynamics of the observed changes, their reversibility, and the occurrence of potential late sequelae.
The correlation between 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) intoxication and the parameters of metabolic impairment was examined in the last eight male survivors of 80 workers exposed to TCDD ...during the production of herbicides in a chemical factory in 1965–1967. Their median TCDD blood level was 112 (46–390) pg/g lipids, and the median TCDD body deposit was 3.9 (0.8–11.7) μg. This puts these patients into the most severely intoxicated group of subjects, according to back‐calculated levels of TCDD. The median TCDD blood level in eight controls was 12 pg/g (<0.10 to 22.2 pg/g). Markers of metabolic impairment – diabetes, dyslipidaemia, arterial hypertension, carotid artery plaque, skin microvascular reactivity, eye fundus hypertensive angiopathy and history of coronary heart disease – were assessed and compared to a general male population of comparable age. Measured parameters compared with a population of comparable age were as follows: prevalence of diabetes (62.5% versus 17.6%), arterial hypertension (87.5% versus 71.8%), dyslipidaemia (87.5% versus 88.8%), history of coronary heart disease (62.5% versus 26.0%) and eye fundus hypertension angiopathy (50% versus 14%). All eight patients (100% versus 43%) developed plaques in carotid arteries, six had stenosis >50% and two had a carotid intervention (stenting or endarterectomy). Total cholesterol levels decreased compared to the earlier study this patient group in 2008, most likely due to a more intensive use of lipid‐lowering drugs. Several metabolic parameters were higher (diabetes as much as 3.5‐fold) in the group of severely TCDD‐intoxicated subjects than in a general population of comparable age. This suggests that TCDD plays a role in the development of metabolic impairment and vascular changes.
•Necrosis of basal ganglia are the typical MRI finding in survivors of methanol poisoning.•Survivors with toxic brain damage had lower volume of basal ganglia.•Positive correlation between the volume ...of putamen, markers of severity of poisoning.•Correlation between the basal ganglia volume and the thickness of retinal nerve fibers layer.
Basal ganglia lesions are typical findings on magnetic resonance imaging (MRI) of the brain in survivors of acute methanol poisoning. However, no data are available on the association between the magnitude of damaged brain regions, serum concentrations of markers of acute methanol toxicity, oxidative stress, neuroinflammation, and the rate of retinal nerve ganglion cell loss.
To investigate the association between MRI-based volumetry of the basal ganglia, retinal nerve fibre layer (RNFL) thickness and prognostic laboratory markers of outcomes in acute methanol poisoning.
MRI-based volumetry of putamen, nucleus caudatus and globus pallidus was performed and compared with laboratory parameters of severity of poisoning and acute serum markers of oxidative damage of lipids (8-isoprostan, MDA, HHE, HNE), nucleic acids (8−OHdG, 8−OHG, 5−OHMU), proteins (o-Thyr, NO-Thyr, Cl-Thyr) and leukotrienes (LTC4, LTD4, LTE4, LTB4), as well as with the results of RNFL measurements by optic coherence tomography (OCT) in 16 patients with acute methanol poisoning (Group I) and in 28 survivors of poisoning two years after discharge with the same markers measured within the follow-up examination (Group II). The control group consisted of 28 healthy subjects without methanol poisoning.
The survivors of acute methanol poisoning had significantly lower volumes of basal ganglia than the controls. The patients with MRI signs of methanol-induced toxic brain damage had significantly lower volumes of basal ganglia than those without these signs. A positive correlation was found between the volume of putamen and arterial blood pH on admission (r = 0.45; p = 0.02 and r = 0.44; p = 0.02 for left and right putamen, correspondingly). A negative correlation was present between the volumes of putamen and acute serum lactate (r = -0.63; p < 0.001 and r = -0.59; p = 0.01), creatinine (r = -0.53; p = 0.01 and r = -0.47; p = 0.01) and glucose (r = -0.55; p < 0.001 and r = -0.50; p = 0.01) concentrations.
The volume of basal ganglia positively correlated with acute concentrations of markers of lipoperoxidation (8-isoprostan: r = 0.61; p < 0.05 and r = 0.59; p < 0.05 for left and right putamen, correspondingly) and inflammation (leukotriene LTB4: r = 0.61; p < 0.05 and r = 0.61; p < 0.05 for left and right putamen, correspondingly). The higher the volume of the basal ganglia, the higher the thickness of the RNFL, with the strongest positive association between global RNFL and the volume of putamen bilaterally (all p < 0.01). In the follow-up markers of oxidative stress and inflammation, only o-Thyr concentration negatively correlated with the volume of putamen bilaterally (r = –0.39; p < 0.05 and r = –0.37; p < 0.05 for left and right putamen, correspondingly).
In survivors of acute methanol poisoning with signs of toxic brain damage, the magnitude of affected areas correlated with acute parameters of severity of poisoning, markers of oxidative stress and neuroinflammation. There was a positive association between the basal ganglia volume and the thickness of RNFL, making OCT an important screening test and MRI-based volumetry the confirmative diagnostic method for the detection of CNS sequelae of methanol poisoning.
To study the dynamics and clinical determinants of chronic retinal nerve fiber layer thickness (RNFL) loss after methanol-induced optic neuropathy.
Prospective cohort study.
All patients underwent ...complete ophthalmic evaluation including spectral-domain optical coherence tomography 3 times during 4 years of observation: 4.9 (±0.6), 25.0 (±0.6), and 49.9 (±0.5) months after discharge. Participants: Eighty-four eyes of 42 survivors of methanol poisoning, mean age (standard deviation) of 45.7 (±4.4) years; and 82 eyes of 41 controls, mean age 44.0 (±4.2) years. Main Outcome Measures: Global and temporal RNFL loss.
Abnormal RNFL thickness was registered in 13 of 42 (31%) survivors of methanol poisoning and chronic axonal loss in 10 of 42 (24%) patients. Significant decrease of global/temporal RNFL thickness during the observation period was found in the study population compared to the controls (P < .001). The risk estimate of chronic global RNFL loss for arterial blood pH < 7.3 at admission was 11.65 (95% confidence interval 1.91–71.12) after adjusting for age and sex. The patients with chronic axonal degeneration demonstrated progressive visual loss in 7 of 10 cases. The patients with abnormal RNFL thickness had magnetic resonance signs of brain damage in 10 of 13 vs 8 of 29 cases with normal RNFL thickness (P = .003). Signs of brain hemorrhages were present in 7 of 13 patients with abnormal RNFL thickness vs 5 of 29 cases with normal RNFL thickness (P = .015).
Methanol-induced optic neuropathy may lead to chronic retinal axonal loss during the following years. Arterial blood pH on admission is the strongest predictor of chronic RNFL thickness decrease. Chronic retinal neurodegeneration is associated with the progressive loss of visual functions and necrotic brain lesions.
Abstract
Objectives. Methanol poisonings occur frequently globally, but reports of larger outbreaks where complete clinical and laboratory data are reported remain scarce. The objective of the ...present study was to report the data from the mass methanol poisoning in the Czech Republic in 2012 addressing the general epidemiology, treatment, and outcomes, and to present a protocol for the use of fomepizole ensuring that the antidote was provided to the most severely poisoned patients in the critical phase. Methods. A combined prospective and retrospective case series study of 121 patients with confirmed methanol poisoning. Results. From a total of 121 intoxicated subjects, 20 died outside the hospital and 101 were hospitalized. Among them, 60 survived without, and 20 with visual/CNS sequelae, whereas 21 patients died. The total and hospital mortality rates were 34% and 21%, respectively. Multivariate regression analysis found pH < 7.0 (OR 0.04 (0.01-0.16), p < 0.001), negative serum ethanol (OR 0.08 (0.02-0.37), p < 0.001), and coma on admission (OR 29.4 (10.2-84.6), p < 0.001) to be the only independent parameters predicting death. Continuous hemodialysis was used more often than intermittent hemodialysis, but there was no significant difference in mortality rate between the two 29% (n = 45) vs 17% (n = 30), p = 0.23. Due to limited stockpiles of fomepizole, ethanol was administered more often; no difference in mortality rate was found between the two 16% (n = 70) vs. 24% (n = 21), p = 0.39. The effect of folate administration both on the mortality rate and on the probability of visual sequelae was not significant (both p > 0.05). Conclusions. Severity of metabolic acidosis, state of consciousness, and serum ethanol on admission were the only significant parameters associated with mortality. The type of dialysis or antidote did not appear to affect mortality. Recommendations that were issued for hospital triage of fomepizole administration allowed conservation of valuable antidote in this massive poisoning outbreak for those patients most in need.
Purpose
In this prospective observational comparative case series, we aimed to study the peripapillary capillary network with spectral‐domain optical coherence tomography angiography (OCT‐A) in Leber ...hereditary optic neuropathy (LHON).
Methods
Twelve eyes of six individuals, of these three males (five eyes) after clinical onset of visual impairment were imaged by OCT‐A with scans centred on optic discs. Control group consisted of 6 eyes with no visual impairment.
Results
The three affected individuals lost vision 6 years (at age 22 years), 2 years and 3 months (at age 26 years) and 1 year and 2 months (at age 30 years) prior to OCT‐A examination. All five affected eyes had alterations in density of the radial peripapillary microvascular network at the level of retinal nerve fibre layer, including an eye of a patient treated with idebenone that underwent almost full recovery (best corrected visual acuity 0.87). Interestingly, the other eye showed normal ocular findings 14 months after onset. Results of OCT‐A examination in this eye were unfortunately inconclusive due to a delineation error. At the level of the ganglion cell layer differences could be also noted, but only in two severely affected individuals. There were no differences between unaffected mutation carriers and control eyes.
Conclusion
Optical coherence tomography angiography scans confirmed that the peripapillary microvascular network is highly abnormal in eyes manifesting visual impairment due to LHON. These findings support the hypothesis that microangiopathy contributes to the development of vision loss in this mitochondrial disorder.
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 (C
max
) LT concentrations were higher than concentrations in survivors: C
max
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.
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.
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