Thiamine as a Possible Neuroprotective Strategy in Neonatal Hypoxic-Ischemic Encephalopathy

On the basis that similar biochemical and histological sequences of events occur in the brain during thiamine deficiency and hypoxia/ischemia related brain damage, we have planned this review to discuss the possible therapeutic role of thiamine and its derivatives in the management of neonatal hypoxic-ischemic encephalopathy (HIE). Among the many benefits, thiamine per se as antioxidant, given intravenously (IV) at high doses, defined as dosage greater than 100 mg IV daily, should counteract the damaging effects of reactive oxygen and nitrogen species in the brain, including the reaction of peroxynitrite with the tyrosine residues of the major enzymes involved in intracellular glucose metabolism, which plays a key pathophysiological role in HIE in neonates. Accordingly, it is conceivable that, in neonatal HIE, the blockade of intracellular progressive oxidative stress and the rescue of mitochondrial function mediated by thiamine and its derivatives can lead to a definite neuroprotective effect. Because therapeutic hypothermia and thiamine may both act on the latent period of HIE damage, a synergistic effect of these therapeutic strategies is likely. Thiamine treatment may be especially important in mild HIE and in areas of the world where there is limited access to expensive hypothermia equipment.

Protective Role of Vitamin B1 in Doxorubicin-Induced Cardiotoxicity in Rats: Focus on Hemodynamic, Redox, and Apoptotic Markers in Heart

Up until now, the specific mechanisms involved in doxorubicin (DOX)-induced cardiotoxicity have not been fully elucidated. Since thiamine deficiency is associated with myocardial dysfunction and it may lead to cardiomyopathy, we aimed to investigate whether thiamine (Vitamin B1) treatment provides cardioprotection and modulates DOX mediated subchronic cardiotoxicity as well as to determine possible mechanisms of its effects. The study involved 48 Wistar albino rats divided into four groups: healthy non-treated rats and healthy rats treated with thiamine and DOX rats without treatment and DOX rats treated with thiamine. DOX was applied as a single i.p.injection (15mg/kg), while thiamine treatment lasted 7days (25mg/kg/dayi.p.). Before and after the treatment hemodynamic changes were monitored in vivo by echocardiography. When the protocol was completed, animals were sacrificed and rat hearts were isolated in order to evaluate parameters of cardiac oxidative stress [superoxide anion radical-O2−, hydrogen peroxide-H2O2, nitric oxide-NO−, index of lipid peroxidation-thiobarbituric acid (TBA) reactive substances (TBARS), superoxide dismutase – SOD, catalase (CAT), and reduced glutathione-GSH] and apoptosis (Bax, Bcl-2, caspases). DOX treatment significantly reduced the ejection fraction, while thiamine treatment led to its minor increase in the DOX-treated group. In that sense, heart oxidative stress markers were significantly increased in DOX-treated rats, while therapeutic dose of thiamine decreased the levels of free radicals. Our study demonstrated the promising ameliorative effects of thiamine against DOX-induced cardiotoxicity through modulation of oxidative stress, suppression of apoptosis, and possibility to improve myocardial performance and morphometric structure of rats` hearts.

Associations between early thiamine administration and clinical outcomes in critically ill patients with acute kidney injury

Background: The effects of early thiamine use on clinical outcomes in critically ill patients with acute kidney injury (AKI) are unclear. The purpose of this study was to investigate the associations between early thiamine administration and clinical outcomes in critically ill patients with AKI. Methods: The data of critically ill patients with AKI within 48 hours after ICU admission were extracted from the Medical Information Mart for Intensive Care III (MIMIC III) database. Propensity score matching (PSM) was used to match patients early receiving thiamine treatment to those not early receiving thiamine treatment. The association between early thiamine use and in-hospital mortality due to AKI was determined using a logistic regression model. Results: A total of 15,066 AKI patients were eligible for study inclusion. After PSM, 734 pairs of patients who did and did not receive thiamine treatment in the early stage were established. Early thiamine use was associated with lower in-hospital mortality (OR 0.65; 95% CI 0.49-0.87; P < 0.001) and 90-day mortality (OR 0.58; 95% CI 0.45-0.74; P < 0.001), and it was also associated with the recovery of renal function (OR 1.26; 95% CI 1.17-1.36; P < 0.001). In the subgroup analysis, early thiamine administration was associated with lower in-hospital mortality in patients with stage 1 to 2 AKI. Conclusions: Early thiamine use was associated with improved short-term survival in critically ill patients with AKI. It was possible beneficial role in patients with stage 1 to 2 AKI according to the KDIGO criteria.

Early Vitamin C, Hydrocortisone, and Thiamine Treatment for Septic Cardiomyopathy: A Propensity Score Analysis

This study investigated the effectiveness of early vitamin C, hydrocortisone, and thiamine among patients with septic cardiomyopathy. In total, 91 patients with septic cardiomyopathy received a vitamin C protocol in September 2018–February 2020. These patients were compared to 75 patients with septic cardiomyopathy who did not receive a vitamin C protocol in September 2016–February 2018. Relative to the control patients, the treated patients were older and more likely to require mechanical ventilation. The vitamin C protocol was associated with a lower risk of intensive care unit mortality in the propensity score (PS)-matched cohort (aHR: 0.55, 95% CI: 0.30–0.99) and inverse probability of treatment weighting-matched cohort (aHR: 0.67, 95% CI: 0.45–1.00). In the PS-matched cohort (59 patients per group), the vitamin C protocol was associated with decreased values for vasopressor dosage, C-reactive protein concentration, and the Sequential Organ Failure Assessment score during the 4-day treatment period. Patients who started the vitamin C protocol within 2 h after diagnosis (vs. 2–8 h or ≥8 h) had the highest vasopressor weaning rate and the lowest mortality rate. These results suggest that early treatment using a vitamin C protocol might improve organ dysfunction and reduce mortality among patients with septic cardiomyopathy.

Ifosfamide-related encephalopathy with severe clinical presentations in children with cancer

Introduction Ifosfamide is an alkylating agent, mostly used against variety of solid tumors in pediatric oncology practice. Although hemorrhagic cystitis is known as a common adverse effect, encephalopathy is the another one that should be kept in mind. It may occur in 2–5% of the children, and manifested by different clinical spectrums such as somnolence, lethargy, irritability, excitement, disorientation, confusion, weakness, hallucinations, seizures, movement disorders, and coma. Case report Herein, we present two patients who developed generalized seizure activity and one who developed coma during ifosfamide infusion. Management and outcome: In the first two patients, ifosfamide infusion was discontinued and intravenous diazepam was given. Their seizure stopped in a few minutes and neurological examination was back to normal, and no focal deficits were observed. In the third patient, ifosfamide infusion was discontinued, methylene blue and thiamine were given. After the tenth dose of methylene blue, she became neurologically normal, without any mental and motor deficit. Nevertheless, later she developed febrile neutropenia, septic shock and she died. Discussion These cases highlight that pediatric oncologists and hematologists should be aware of possibility of severe neurological toxicity after administration of ifosfamide in adolescent patients. Apart from seizure, clinicians should also be prepared to notice drowsiness during ifosfamide infusions in children. Most of the time cessation of ifosfamide and hydration is enough. However, in severe toxicities there is a risk of irreversible neurological damage, and for these patients methylene blue (MB) and thiamine treatment should be kept in mind.

Thiamine Pyrophosphokinase Deficiency due to Mutations in the TPK1 Gene: A Rare, Treatable Neurodegenerative Disorder

TPK deficiency due to TPK1 mutations is a rare neurodegenerative disorder, also known as thiamine metabolism dysfunction syndrome 5 (OMIM no.: 614458). Here, we report a new patient with compound heterozygous TPK1 mutations, of which one has not been described so far. The individual reported here suffered from acute onset encephalopathy, ataxia, muscle hypotonia, and regression of developmental milestones in early infancy, repeatedly triggered by febrile infections. Initiation of high-dose thiamine and magnesium supplementation led to a marked and sustained improvement of alertness, ataxia, and muscle tone within days. Contrary to the described natural history of patients with TPK deficiency, the disease course was favorable under thiamine treatment without deterioration or developmental regression during the follow-up period. TPK deficiency is a severe neurodegenerative disease. This case report demonstrates that this condition is potentially treatable. High-dose thiamine treatment should therefore be initiated immediately after diagnosis or even upon suspicion.

SLC25A19 deficiency and bilateral striatal necrosis with polyneuropathy: a new case and review of the literature

ObjectivesBiallelic mutations in the SLC25A19 gene impair the function of the thiamine mitochondrial carrier, leading to two distinct clinical phenotypes. Homozygosity for the c.530G > C mutation is invariably associated to Amish lethal microcephaly. The second phenotype, reported only in 8 patients homozygous for different non-Amish mutations (c.373G > A, c.580T > C, c.910G > A, c.869T > A, c.576G > C), is characterized by bilateral striatal necrosis and peripheral polyneuropathy. We report a new patient with the non-Amish SLC25A19 phenotype showing compound heterozygosity for the new variant c.673G > A and the known mutation c.373G > A.Case presentationThe natural history of non-Amish SLC25A19 deficiency is characterized by acute episodes of fever-induced encephalopathy accompanied by isolated lactic acidosis and Leigh-like features at magnetic resonance imaging (MRI). Acute episodes are prevented by high-dose thiamine treatment (600 mg/day). As shown in the new case, both mild clinical signs and basal ganglia involvement can precede the acute encephalopathic onset of the disease, potentially allowing treatment anticipation and prevention of acute brain damage. Peripheral axonal neuropathy, observed in 7 out of 9 patients, is not improved by thiamine therapy. In two early treated patients, however, peripheral neuropathy did not occur even on long-term follow-up, suggesting a potential preventive role of treatment anticipation also at the peripheral level.ConclusionsNon-Amish SLC25A19 deficiency is an extra-rare cause of Leigh syndrome responsive to thiamine treatment. Ex adiuvantibus thiamine treatment is mandatory in any patient with Leigh-like features.

Thiamine Treatment and Favorable Outcome in an Infant with Biallelic TPK1 Variants

Episodic encephalopathy due to mutations in the thiamine pyrophosphokinase 1 (TPK1) gene is a rare autosomal recessive metabolic disorder. Patients reported so far have onset in early childhood of acute encephalopathic episodes, which result in a progressive neurologic dysfunction including ataxia, dystonia, and spasticity. Here, we report the case of an infant with TPK1 deficiency (compound heterozygosity for two previously described pathogenic variants) presenting with two encephalopathic episodes and clinical stabilization under oral thiamine and biotin supplementation. In contrast to other reported cases, our patient showed an almost normal psychomotor development, which might be due to an early diagnosis and subsequent therapy.

Thiamine deficiency in the outpatient psychiatric oncology setting: A case series

ObjectiveB vitamins are essential for the functioning of the nervous system. Vitamin B1 (thiamine) deficiency is associated with neuropsychiatric syndromes such as Wernicke's encephalopathy (WE), which, if untreated, has an estimated mortality of 17–20%. Although the prevalence of thiamine deficiency in the general population is difficult to estimate, it is being increasingly recognized in oncology, especially in the inpatient setting. We describe three cases of thiamine deficiency (TD) in the outpatient psychiatric oncology setting.MethodRetrospective chart review of three adult patients, who were seen in the psychiatric oncology clinic and found to have TD on laboratory testing, was done. Patient, disease, and thiamine treatment-related information were obtained, and descriptive statistics were used to analyze the data.ResultsThe average age was 59 years, mean body mass index (BMI) was 22.00 ± 4.58 (mean ± SD), and mean thiamine level was 59.10 ± 7.69 that ranged from 45 to 68 nmol/L (normal thiamine level reference: 70–180 nmol/L). None of the patients had brain imaging nor cerebrospinal fluid analysis. Risk factors such as unbalanced nutrition, prior GI surgery, renal disease, and chemotherapy were noted.Significance of resultsTD can have a multifactorial etiology in oncology. Identification of TD in both inpatient and outpatient setting is important. Our report highlights how early identification of TD in the outpatient setting can help prevent further clinical progression.