Stem Cell Therapy and Thiamine Deficiency-Induced Brain Damage.

Wernicke's encephalopathy (WE) is a major central nervous system disorder resulting from thiamine deficiency (TD) in which a number of brain regions can develop serious damage including the thalamus and inferior colliculus. Despite decades of research into the pathophysiology of TD and potential therapeutic interventions, little progress has been made regarding effective treatment following the development of brain lesions and its associated cognitive issues. Recent developments in our understanding of stem cells suggest they are capable of repairing damage and improving function in different maladys. This article puts forward the case for the potential use of stem cell treatment as a therapeutic strategy in WE by first examining the effects of TD on brain functional integrity and its consequences. The second half of the paper will address the future benefits of treating TD with these cells by focusing on their nature and their potential to effectively treat neurodegenerative diseases that share some overlapping pathophysiological features with TD. At the same time, some of the obstacles these cells will have to overcome in order to become a viable therapeutic strategy for treating this potentially life-threatening illness in humans will be highlighted.

Clinical diagnosis, outcomes and treatment of thiamine deficiency in a tertiary hospital.

BACKGROUND: Acute thiamine deficiency can occur in patients with or without history of alcohol abuse and can lead to life-threatening complications. Clinical diagnosis is challenging, often resulting in delayed recognition and treatment. Patients may present with heterogenous symptoms, more diverse than the historical neurological description. Cerebral MRI can contribute to the diagnosis in patients with neurological signs but it is not always feasible in emergency settings. Prompt parenteral supplementation is required to obtain the improvement of symptoms and avoid chronic complications. AIMS: To describe the clinical presentation of reported cases of thiamine deficiency, assess prescription and results of cerebral imaging, review treatments that had been prescribed in accordance or not with available guidelines, and study the short-term outcome of these patients. METHODS: This is a monocentric retrospective analysis of all reported cases of thiamine deficiency in a French tertiary hospital between January 1st 2008 and December 31st 2018. RESULTS: Fifty-six cases were identified during the study period. Forty-five (80%) patients had a history of alcohol abuse. Most patients were diagnosed based on neurological symptoms but non-specific and digestive symptoms were frequent. Thirty-four percent of patients fulfilled clinical criteria for malnutrition. A brain MRI was performed in 54% of patients and was abnormal in 63% of these cases. Eighty-five percent of patients were treated by parenteral thiamine administration and the supplementation was continued orally in 55% of them. The majority of patients initially received 1000 mg daily of IV thiamine but the dose and duration of thiamine supplementation were variable. At the time of discharge, partial or complete improvement of symptoms was noted in 59% of patients. CONCLUSION: This study highlights the clinical and radiological heterogeneity of thiamine deficiency. These observations should encourage starting thiamine supplementation early in patients with risk factors or suggestive symptoms even in non-alcoholic patients, and underline the importance of early nutritional support.

Thiamine fortification strategies in low- and middle-income settings: a review.

Thiamine (vitamin B1 ) is an essential micronutrient in energy metabolism and cognitive and neurological health. Thiamine deficiency disorders (TDDs) have a range of clinical presentations that result in various morbidities and can be fatal if not promptly recognized and treated, especially in infants. To intervene, thiamine intakes by breastfeeding mothers and others at risk of thiamine deficiency should be increased to ensure adequate thiamine intake. Although thiamine fortification programs have a long history in high-income countries, there are few mandatory fortification programs to address TDDs in low- and middle-income countries (LMICs), particularly in the regions of greatest concern, South and Southeast Asia. This review highlights essential aspects for consideration in the development of a mandatory fortification program in LMICs, including an overview of the data required to model fortification dosing schemes, available thiamine fortificants, and potential fortification vehicles, as well as identifies current knowledge gaps.

Thiamine deficiency disorders: a clinical perspective.

Thiamine is an essential water-soluble vitamin that plays an important role in energy metabolism. Thiamine deficiency presents many challenges to clinicians, in part due to the broad clinical spectrum, referred to as thiamine deficiency disorders (TDDs), affecting the metabolic, neurologic, cardiovascular, respiratory, gastrointestinal, and musculoskeletal systems. Concurrent illnesses and overlapping signs and symptoms with other disorders can further complicate this. As such, TDDs are frequently misdiagnosed and treatment opportunities missed, with fatal consequences or permanent neurologic sequelae. In the absence of specific diagnostic tests, a low threshold of clinical suspicion and early therapeutic thiamine is currently the best approach. Even in severe cases, rapid clinical improvement can occur within hours or days, with neurological involvement possibly requiring higher doses and a longer recovery time. Active research aims to help better identify patients with thiamine-responsive disorders and future research is needed to determine effective dosing regimens for the various clinical presentations of TDDs. Understanding the clinical diagnosis and global burden of thiamine deficiency will help to implement national surveillance and population-level prevention programs, with education to sensitize clinicians to TDDs. With concerted effort, the morbidity and mortality related to thiamine deficiency can be reduced.

[The knowledge of resident doctors on diagnostics, etiology and treatment of Wernicke encephalopathy]. / De kennis van a(n)iossen over diagnostiek, etiologie en behandeling van wernicke-encefalopathie.

BACKGROUND: Wernicke encephalopathy (we) is a severe, acute neuropsychiatric disorder caused by a deficiency in thiamine. There have been indications that we is undertreated, which can lead to the Korsakoff syndrome, delirium or death. Treatment according to protocol is simple and effective. The knowledge of physicians about we has not been researched before.
AIM: To test the knowledge of resident doctors on diagnosis, etiology and treatment of we.
METHOD: The knowledge of 70 resident doctors in different medical specialties was examined through two clinical cases: the first with we due to hyperemesis gravidarum and the second due to alcohol abuse. Both open and multiple-choice questions were asked. Cues of the classical triad of we (cognitive disorder, eye movement disorder and gait disorder) were given accumulatively.
RESULTS: The classical triad of we was not recognized by 73% of the resident doctors in the case of hyperemesis gravidarum and they missed we in the case of alcohol abuse. Many of the resident doctors were not able to name the thiamin deficiency, the triad of we, more than three causes of we or the correct treatment with thiamine sufficiently. 67% of resident doctors indicated that their knowledge of we was insufficient and 76% expressed a need for more information about we.
CONCLUSION: The knowledge of resident doctors about the diagnostics, etiology and management of we is insufficient. Moreover, the resident doctors evaluate their knowledge about we to be insufficient. Medical school and postgraduate specialization have to focus more on this common and severe syndrome, which can appear in different medical areas.

Subclinical thiamine deficiency: What is the most appropriate method of diagnosis and treatment?

OBJECTIVES: The symptoms of thiamine deficiency vary considerably and asymptomatic cases; i.e., subclinical thiamine deficiency (SCTD), are known to exist. However, there is no information available on the treatment of SCTD. METHODS: We report a patient who underwent intravenous thiamine replacement therapy for about a month after being diagnosed with SCTD, but who developed SCTD again about three weeks after finishing the treatment. RESULTS: The patient was a 64-year-old woman who, after starting treatment for cervical cancer, complained of anxiety and underwent an initial psychiatric examination. The psychiatric diagnosis was an adjustment disorder. Based on the possibility of SCTD complications due to her decreased appetite and weight loss, her serum thiamine concentration was measured and found to be low. Therefore, thiamine was administered intravenously for 29 days. At the end of treatment, thiamine administration was discontinued as there were no apparent neuropsychiatric symptoms or problems with appetite. Twenty-three days later, there were still no problems with appetite or neuropsychiatric symptoms, but a follow-up blood sample revealed that her serum thiamine was again below the normal range. SIGNIFICANCE OF RESULTS: Currently, there is no information available regarding the diagnosis and treatment of SCTD in cancer patients. In some cases, such as this case, the deficiency recurs without any symptoms indicative of SCTD; therefore, further examination for diagnosis and treatment is necessary.

Pathophysiology, prevention, and treatment of beriberi after gastric surgery.

Beriberi is a nutritional complication of gastric surgery, caused by deficiency of vitamin B1, or thiamine. Thiamine deficiency leads to impaired glucose metabolism, decreased delivery of oxygen by red blood cells, cardiac dysfunction, failure of neurotransmission, and neuronal death. This review describes the history and pathophysiology of beriberi as well as the relationship between beriberi and nutritional deficiencies after gastric surgery. A literature review of the history and pathophysiology of beriberi and the risk factors for thiamine deficiency, particularly after gastric resection or bariatric surgery, was performed. Recommendations for nutritional follow-up post gastric surgery are based on current national guidelines. Patients may have subclinical thiamine deficiency after upper gastrointestinal surgery, and thus beriberi may be precipitated by acute illness such as sepsis or poor dietary intake. This may occur very soon or many years after gastrectomy or bariatric surgery, even in apparently well-nourished patients. Prompt recognition and administration of supplemental thiamine can decrease morbidity and mortality in patients with beriberi. Dietary education post surgery and long-term follow-up to determine nutritional status, including vitamin and mineral assessment, is recommended for patients who undergo gastric surgery.

Early recognition of thiamine deficiency: ocular motor deficits in a patient with nutritional deprivation due to persistent antibiotic-related nausea.

CASE DESCRIPTION: A 73-year-old male presented with new onset dizziness and a 22-kg weight loss due to antibiotic-induced nausea/vomiting. Due to gaze-evoked nystagmus (GEN), thiamine deficiency was suspected. Within 12 h after replacement, his GEN decreased. CONCLUSION: In patients with nutritional deprivation, new onset GEN should prompt further diagnostics and immediate thiamine supplementation to avoid disease progression.

Infantile Thiamine Deficiency: New Insights into an Old Disease.

CONTEXT: The wide spectrum of clinical presentation in infantile thiamine deficiency is difficult to recognize, and the diagnosis is frequently missed due to the lack of widespread awareness, and non-availability of costly and technically demanding investigations. EVIDENCE ACQUISITION: The topic was searched by two independent researchers using online databases of Google scholar and PubMed. We considered the related studies published in the last 20 years. The terms used for the search were 'thiamine', 'thiamine deficiency', 'beri-beri', 'B-vitamins','micronutrients', 'malnutrition', 'infant mortality'. 'Wernicke's syndrome','Wernicke's encephalopathy', and 'lactic acidosis'. RESULTS: In the absence of specific diagnostic tests, a low threshold for a therapeutic thiamine challenge is currently the best approach to diagnose infantile thiamine deficiency in severe acute conditions. The practical approach is to consider thiamine injection as a complementary resuscitation tool in infants with severe acute conditions; more so in presence of underlying risk factors, clinically evident malnutrition or where a dextrose-based fluid is used for resuscitation. Further, as persistent subclinical thiamine deficiency during infancy can have long-term neuro-developmental effects, reasonable strategy is to treat pregnant women suspected of having the deficiency, and to supplement thiamine in both mother and the baby during breastfeeding. CONCLUSIONS: Health care professionals in the country need to be sensitized to adopt a high level of clinical suspicion for thiamine deficiency and a low threshold for the administration of thiamine, particularly when infantile thiamine deficiency is suspected.

Complete recovery in Wernicke's encephalopathy complicating hyperemesis gravidarum.

Wernicke's encephalopathy (WE) is an uncommon neurological complication in pregnancies complicated with hyperemesis due to thiamine deficiency. In women with hyperemesis, inadvertent glucose administration prior to thiamine supplementation triggers the development of neurological manifestations. Delay in the diagnosis can lead to maternal morbidity, and in one-third of cases may lead to persistence of some neurological deficit. With early recognition and thiamine supplementation, complete recovery is reported. We report a case of WE complicating a case of triplet pregnancy with hyperemesis gravidarum, which highlights the importance of early recognition and treatment, resulting in complete recovery as in the index case.

[Thiamine-responsive megaloblastic anemia or Rogers syndrome: A literature review]. / L'anémie mégaloblastique thiamine dépendante ou syndrome de Rogers : une revue de la littérature.

Thiamine-responsive megaloblastic anemia (TRMA), also known as Rogers syndrome, is a rare autosomal recessive disease characterized by three main components: megaloblastic anemia, diabetes mellitus and sensorineural deafness. Those features occur in infancy but may arise during adolescence. Diagnosis relies on uncovering genetic variations (alleles) in the SLC19A2 gene, encoding for a high affinity thiamine transporter. This transporter is essentially present in hematopoietic stem cells, pancreatic beta cells and inner ear cells, explaining the clinical manifestations of the disease. Based on a multidisciplinary approach, treatment resides on lifelong thiamine oral supplementation at pharmacological doses, which reverses anemia and may delay development of diabetes. However, thiamine supplementation does not alleviate already existing hearing defects.

Thiamine deficiency disorders: diagnosis, prevalence, and a roadmap for global control programs.

Thiamine is an essential micronutrient that plays a key role in energy metabolism. Many populations worldwide may be at risk of clinical or subclinical thiamine deficiencies, due to famine, reliance on staple crops with low thiamine content, or food preparation practices, such as milling grains and washing milled rice. Clinical manifestations of thiamine deficiency are variable; this, along with the lack of a readily accessible and widely agreed upon biomarker of thiamine status, complicates efforts to diagnose thiamine deficiency and assess its global prevalence. Strategies to identify regions at risk of thiamine deficiency through proxy measures, such as analysis of food balance sheet data and month-specific infant mortality rates, may be valuable for understanding the scope of thiamine deficiency. Urgent public health responses are warranted in high-risk regions, considering the contribution of thiamine deficiency to infant mortality and research suggesting that even subclinical thiamine deficiency in childhood may have lifelong neurodevelopmental consequences. Food fortification and maternal and/or infant thiamine supplementation have proven effective in raising thiamine status and reducing the incidence of infantile beriberi in regions where thiamine deficiency is prevalent, but trial data are limited. Efforts to determine culturally and environmentally appropriate food vehicles for thiamine fortification are ongoing.

Thiamine status, metabolism and application in dairy cows: a review.

As the co-enzyme of pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, thiamine plays a critical role in carbohydrate metabolism in dairy cows. Apart from feedstuff, microbial thiamine synthesis in the rumen is the main source for dairy cows. However, the amount of ruminal thiamine synthesis, which is influenced by dietary N levels and forage to concentrate ratio, varies greatly. Notably, when dairy cows are overfed high-grain diets, subacute ruminal acidosis (SARA) occurs and results in thiamine deficiency. Thiamine deficiency is characterised by decreased ruminal and blood thiamine concentrations and an increased blood thiamine pyrophosphate effect to >45 %. Thiamine deficiency caused by SARA is mainly related to the increased thiamine requirement during high grain feeding, decreased bacterial thiamine synthesis in the rumen, increased thiamine degradation by thiaminase, and decreased thiamine absorption by transporters. Interestingly, thiamine deficiency can be reversed by exogenous thiamine supplementation in the diet. Besides, thiamine supplementation has beneficial effects in dairy cows, such as increased milk and component production and attenuated SARA by improving rumen fermentation, balancing bacterial community and alleviating inflammatory response in the ruminal epithelium. However, there is no conclusive dietary thiamine recommendation for dairy cows, and the impacts of thiamine supplementation on protozoa, solid-attached bacteria, rumen wall-adherent bacteria and nutrient metabolism in dairy cows are still unclear. This knowledge is critical to understand thiamine status and function in dairy cows. Overall, the present review described the current state of knowledge on thiamine nutrition in dairy cows and the major problems that must be addressed in future research.

A diagnosis and treatment gap for thiamine deficiency disorders in sub-Saharan Africa?

Staple diets that are deficient in thiamine can result in low body thiamine levels, which may be subclinical or may manifest as a thiamine-deficiency syndrome. In many communities in the developing countries of Africa, the staple diets of polished rice or processed cassava are deficient in thiamine, and thus the communities are at high risk for marginal or frank thiamine deficiency unless their diets are supplemented by other sources of thiamine, such as protein meals and vegetables. African communities with large numbers of individuals in low socioeconomic strata are more likely to subsist on a monotonous diet of rice or cassava with minimal or no protein supplementation and are therefore particularly at risk of thiamine-deficiency disorders. Indeed, there is evidence of widespread biochemical thiamine deficiency from community-based studies in Africa. The protean manifestations of thiamine deficiency disorders in the developing countries of Africa are presented in this paper. We present evidence supporting the contention that there is a diagnosis and treatment gap for thiamine-deficiency disorders in Africa. We discuss research and clinical options for bridging the putative diagnosis and treatment gap for thiamine-deficiency disorders in the developing countries of Africa.

Cortical damage in Wernicke's encephalopathy with good prognosis: a report of two cases and literature review.

Wernicke's encephalopathy (WE) is a thiamine deficiency-related condition, in which lesions are usually present in the periventricular and subcortical areas of the brain. However, lesions have also been found in atypical areas, such as the cerebral cortex. The present study summarizes the clinical outcomes and radiological features of WE with cortical impairment. We report two cases of cortical involvement in patients with WE, and review 22 similar cases from other reports. Among all 24 cases, 4 patients had a confirmed history of chronic daily alcohol abuse, and 19 of them had an identified causes of thiamine deficiency. 17 cases reported specific clinical information, among which 11 patients had symptoms of cortical impairment. 23 cases reported prognostic information at the end of treatment or at follow-up. The mortality rate was 26.1 % in our review. All patients had abnormal magnetic resonance imaging (MRI) signals or pathological findings in the bilateral cortex. Among patients with available MRI, 89.0 % had banding-like signs along the para-central sulcus. 13 cases underwent follow-up MRI examinations and 76.9 % displayed normal images. We suggest that WE with bilateral cortical involvement may have an acceptable prognosis, but that the mortality rate is higher than that among typical cases, especially if patients are not treated promptly and correctly. We identified the frontal and parietal lobes, especially around the central sulcus, to be the most susceptible areas, and suggest that the banding signs may be characteristic of WE. Persistent hyper-intensity on T2-weighted-fluid-attenuated inversion recovery, or gadolinium enhancement, may predict poor outcome.

Encefalopatía de Wernicke como complicación de hiperémesis gravídica / Wernicke’s encephalopathy as complication of hyperemesis gravidarum

Los hallazgos de la encefalopatía de Wernicke han sido descritos como una combinación de confusión, anomalías oculares y ataxia. La encefalopatía puede complicar la hiperémesis gravídica debido a que esta altera la absorción correcta de una cantidad adecuada de tiamina y puede causar alteraciones electrolíticas. Se presenta el caso de una primigesta de 22 años de edad que fue hospitalizada por presentar letargia, debilidad generalizada, oftalmoplejía, alteraciones del lenguaje y pérdida de peso a las 12 semanas de embarazo. Tenía antecedentes de hiperémesis gravídica tres semanas antes de la hospitalización. El examen físico reveló una paciente letárgica con nistagmos horizontales, ataxia e hiporeflexia simétrica. Se inició tratamiento con tiamina. La paciente se recuperó de las alteraciones neurológicas 6 semanas después del tratamiento (AU)

The features of Wernicke’s encephalopathy have been described as a combination of confusion, ocular abnormalities, and ataxia. Encephalopathy can complicate hyperemesis gravidarum because it impairs correct absorption of an adequate amount of thiamine and can cause electrolyte imbalance. We present the case of a 22-year-old primipara who was admitted to hospital due to lethargy, generalized weakness, ophthalmoplegia, language disturbance, and weight loss in her 12th week of pregnancy. The patient had a history of hyperemesis gravidarum three weeks before admission. Physical examination revealed a lethargic patient with horizontal nystagmus, ataxia, and symmetric hyporeflexia. Parenteral thiamine therapy was started. The patient recovered from the neurological deficits after 6 weeks of treatment (AU)

Treatable Inborn Errors of Metabolism Due to Membrane Vitamin Transporters Deficiency.

B vitamins act as cofactors for strategic metabolic processes. The SLC19 gene family of solute carriers has a significant structural similarity, transporting substrates with different structure and ionic charge. Three proteins of this family are expressed ubiquitously and mediate the transport of 2 important water-soluble vitamins, folate, and thiamine. SLC19A1 transports folate and SLC19A2 and SLC19A3 transport thiamine. PCFT and FOLR1 ensure intestinal absorption and transport of folate through the blood-brain barrier and SLC19A25 transports thiamine into the mitochondria. Several damaging genetic defects in vitamin B transport and metabolism have been reported. The most relevant feature of thiamine and folate transport defects is that both of them are treatable disorders. In this article, we discuss the biology and transport of thiamine and folate, as well as the clinical phenotype of the genetic defects.

Vitamin B deficiencies in a critically ill autistic child with a restricted diet.

An 11-year-old male with autism became less responsive and was hospitalized with hepatomegaly and liver dysfunction, as well as severe lactic acidosis. His diet for several years was self-limited exclusively to a single "fast food"-a particular type of fried chicken-and was deficient in multiple micronutrients, including the B vitamins thiamine and pyridoxine. Lactic acidosis improved rapidly with thiamine; 2 weeks later, status epilepticus-with low serum pyridoxine-resolved rapidly with pyridoxine. Dietary B vitamin deficiencies complicated the care of this critically ill autistic child and should be considered in this setting.

Thiamine deficiency: an update of pathophysiologic mechanisms and future therapeutic considerations.

Thiamine is an essential vitamin that is necessary to maintain the functional integrity of cells in the brain. Its deficiency is the underlying cause of Wernicke's encephalopathy (WE), a disorder primarily associated with, but not limited to, chronic alcoholism. Thiamine deficiency leads to the development of impaired energy metabolism due to mitochondrial dysfunction in focal regions of the brain resulting in cerebral vulnerability. The consequences of this include oxidative stress, excitotoxicity, inflammatory responses, decreased neurogenesis, blood-brain barrier disruption, lactic acidosis and a reduction in astrocyte functional integrity involving a loss of glutamate transporters and other astrocyte-specific proteins which together contribute in a major way to the resulting neurodegeneration. Exactly how these factors acting in concert lead to the demise of neurons is unclear. In this review we reassess their relative importance in the light of more recent findings and discuss therapeutic possibilities that may provide hope for the future for individuals with WE.