Hyperemesis-induced Wernicke-Korsakoff Syndrome due to Hypergastrinemia during Long-term Treatment with Proton Pump Inhibitors.

We herein report a patient with Wernicke-Korsakoff syndrome (WKS) who had neither a history of alcoholism or of history of gastric surgery. A 56-year-old woman was transferred to our hospital because of the loss of consciousness and she was diagnosed to have Wernicke encephalopathy. She showed proton pump inhibitor-induced refractory hypergastrinemia with the subsequent development of hyperemesis and a vitamin B1 deficiency.

Current and future role of fedratinib in the treatment of myelofibrosis.

Fedratinib (INREBIC® [fedratinib] capsules, Impact Biomedicines, Inc., a wholly owned subsidiary of Celgene Corporation), is a potent JAK2 inhibitor that has been approved for use in myelofibrosis, both as a first-line agent and also in second line following ruxolitinib (Novartis Pharmaceuticals, Basel, Switzerland) failure or intolerance. Within this article, we will review relevant preclinical and early/late clinical trial data concerning the use of fedratinib to treat myeloproliferative neoplasms. Moreover, we will review in detail the assumed safety issues that led to temporary cessation of all programs with the agent in 2013 which subsequently re-entered the clinical arena in 2017. We will discuss how physicians may safely transition a patient across from ruxolitinib to fedratinib following intolerance or lack of efficacy. At last, we will discuss potential future applications of this agent within the field.

Alcohol's Effects on the Brain: Neuroimaging Results in Humans and Animal Models.

Brain imaging technology has allowed researchers to conduct rigorous studies of the dynamic course of alcoholism through periods of drinking, sobriety, and relapse and to gain insights into the effects of chronic alcoholism on the human brain. Magnetic resonance imaging (MRI) studies have distinguished alcohol-related brain effects that are permanent from those that are reversible with abstinence. In support of postmortem neuropathological studies showing degeneration of white matter, MRI studies have shown a specific vulnerability of white matter to chronic alcohol exposure. Such studies have demonstrated white-matter volume deficits as well as damage to selective gray-matter structures. Diffusion tensor imaging (DTI), by permitting microstructural characterization of white matter, has extended MRI findings in alcoholics. MR spectroscopy (MRS) allows quantification of several metabolites that shed light on brain biochemical alterations caused by alcoholism. This article focuses on MRI, DTI, and MRS findings in neurological disorders that commonly co-occur with alcoholism, including Wernicke's encephalopathy, Korsakoff's syndrome, and hepatic encephalopathy. Also reviewed are neuroimaging findings in animal models of alcoholism and related neurological disorders. This report also suggests that the dynamic course of alcoholism presents a unique opportunity to examine brain structural and functional repair and recovery.

Treatment of rats with the JAK-2 inhibitor fedratinib does not lead to experimental Wernicke's encephalopathy.

Recent clinical trials suggest that patients with myelofibrosis can develop Wernicke's encephalopathy (WE) when treated with fedratinib, a specific Janus kinase-2 (JAK-2) inhibitor. To investigate this issue, we have examined (1) if fedratinib can produce or alter the course of this disorder, (2) its effects on thiamine-dependent enzyme activity and thiamine status, and (3) its influence on the uptake of thiamine. Animals administered fedratinib for 28days at a comparable dose used to treat human cases of myelofibrosis showed no evidence of clinical signs of thiamine deficiency (TD). Rats treated with a combination of fedratinib and TD exhibited no neurological differences in their progress to the symptomatic stage when compared to thiamine-deficient animals only. Treatment with the JAK-2 inhibitor did not compromise erythrocyte transketolase activity, and thiamine status was not affected in a major way unlike animals with TD. In addition, treatment of cultured astrocytes with fedratinib did not diminish the uptake of thiamine into these cells. Our findings suggest that treatment with fedratinib does not lead to or alter the progress of TD, and do not support the notion that administration of this JAK-2 inhibitor directly results in the development of WE due to inhibition of thiamine transport. Known adverse effects of fedratinib involving compromised gastrointestinal function may be an important indirect contributing factor to previously reported cases of WE in patients with myelofibrosis.

Putamina involvement in Wernicke encephalopathy induced by Janus Kinase 2 inhibitor.

OBJECTIVE: The aim of the study was to report a case of Wernicke encephalopathy (WE) due to fedratinib (Janus Kinase 2 inhibitor) treatment with atypical neuroimaging findings. METHODS: We present a detailed report of the case and literature review. RESULTS: A 68-year-old woman under treatment with fedratinib (investigational JAK2 inhibitor) developed memory impairment, diplopia, and ataxia compatible with WE. Brain magnetic resonance imaging showed extensive lesions involving medial thalami, periaqueductal gray, caudate nuclei, and putamina. Thiamine supplementation provided clinical recovery and radiological improvement of the lesions described. Basal ganglia lesions have been previously described in children with this disease, but this is rarely found in adults. Clinical trials including fedratinib have been recently discontinued, and its involvement in pathogenesis of WE may be related to thiamine-transporter inhibition. CONCLUSIONS: Our case represents an example of drug-related WE, with a rare radiological pattern. Precocious diagnosis and treatment are essential to prevent irreversible brain injury.

Wernicke encephalopathy and ethanol-related syndromes.

Ethanol causes diverse neurologic conditions caused by acute and chronic brain damage. This review provides an overview of Wernicke encephalopathy and other ethanol-related brain changes, such as chronic brain atrophy, Marchiafava-Bignami disease, osmotic demyelination syndrome, chronic hepatic encephalopathy, and acute alcohol withdrawal. As clinical symptoms of this spectrum of diseases have nonspecific neurologic alterations, radiologists should have current radiologic information and understand the imaging findings pertaining to the pathophysiology to support diagnosis.

Pyrithiamine-induced thiamine deficiency alters proliferation and neurogenesis in both neurogenic and vulnerable areas of the rat brain.

Thiamine deficiency (TD) leads to Wernicke's encephalopathy (WE), in which focal histological lesions occur in periventricular areas of the brain. Recently, impaired neurogenesis has been reported in the hippocampus during the dietary form of TD, and in pyrithiamine-induced TD (PTD), a well-characterized model of WE. To further characterize the consequences of PTD on neural stem/progenitor cell (NSPC) activity, we have examined the effect of this treatment in the rat on both the subventricular zone (SVZ) of the rostral lateral ventricle and subgranular layer (SGL) of the hippocampus, and in the thalamus and inferior colliculus, two vulnerable brain regions in this disorder. In both the SVZ and SGL, PTD led to a decrease in the numbers of bromodeoxyuridine-stained cells, indicating that proliferation of NSPCs destined for neurogenesis in these areas was reduced. Doublecortin (DCX) immunostaining in the SGL was decreased, indicating a reduction in neuroblast formation, consistent with impaired NSPC activity. DCX labeling was not apparent in focal areas of vulnerability. In the thalamus, proliferation of cells was absent while in the inferior colliculus, numerous actively dividing cells were apparent, indicative of a differential response between these two brain regions. Exposure of cultured neurospheres to PTD resulted in decreased proliferation of NSPCs, consistent with our in vivo findings. Together, these results indicate that PTD considerably affects cell proliferation and neurogenesis activity in both neurogenic areas and parts of the brain known to display structural and functional vulnerability, confirming and extending recent findings on the effects of TD on neurogenesis. Future use of NSPCs in vitro may allow a closer and more detailed examination of the mechanism(s) underlying inhibition of these cells during TD.

Focal thalamic degeneration from ethanol and thiamine deficiency is associated with neuroimmune gene induction, microglial activation, and lack of monocarboxylic acid transporters.

BACKGROUND: Wernicke's encephalopathy-Korsakoff syndrome (WE-KS) is common in alcoholics, caused by thiamine deficiency (TD; vitamin B1) and associated with lesions to the thalamus (THAL). Although TD alone can cause WE, the high incidence in alcoholism suggests that TD and ethanol (EtOH) interact. METHODS: Mice in control, TD, or EtOH groups alone or combined were studied after 5 or 10 days of treatment. THAL and entorhinal cortex (ENT) histochemistry and mRNA were assessed. RESULTS: Combined EtOH-TD treatment for 5 days (EtOH-TD5) showed activated microglia, proinflammatory gene induction and THAL neurodegeneration that was greater than that found with TD alone (TD5), whereas 10 days resulted in marked THAL degeneration and microglial-neuroimmune activation in both groups. In contrast, 10 days of TD did not cause ENT degeneration. Interestingly, in ENT, TD10 activated microglia and astrocytes more than EtOH-TD10. In THAL, multiple astrocytic markers were lost consistent with glial cell loss. TD blocks glucose metabolism more than acetate. Acetate derived from hepatic EtOH metabolism is transported by monocarboxylic acid transporters (MCT) into both neurons and astrocytes that use acetyl-CoA synthetase (AcCoAS) to generate cellular energy from acetate. MCT and AcCoAS expression in THAL is lower than ENT prompting the hypothesis that focal THAL degeneration is related to insufficient MCT and AcCoAS in THAL. To test this hypothesis, we administered glycerin triacetate (GTA) to increase blood acetate and found it protected the THAL from TD-induced degeneration. CONCLUSIONS: Our findings suggest that EtOH potentiates TD-induced THAL degeneration through neuroimmune gene induction. The findings support the hypothesis that TD deficiency inhibits global glucose metabolism and that a reduced ability to process acetate for cellular energy results in THAL focal degeneration in alcoholics contributing to the high incidence of Wernicke-Korsakoff syndrome in alcoholism.

A case of Wernicke encephalopathy combined with disulfiram intoxication.

There have been several reports of disulfiram intoxication, but little evidence of neurologic conditions resulting from disulfiram-induced brain damage combined with Wernicke encephalopathy-associated lesions. We report a rare patient with both Wernicke encephalopathy and disulfiram intoxication. This 50-year-old woman, who was taking disulfiram for chronic alcohol abuse, presented with an acute confusional state, dysarthria, nystagmus, supranuclear ophthalmoplegia, and paraparesis. Biochemical serum and cerebrospinal fluid analyses were normal. An electromyogram detected a motor polyneuropathy. Cognitive assessment revealed severe impairment of memory, attention, and logical and executive abilities. Magnetic resonance imaging with gadolinium enhancement showed brain lesions consistent with Wernicke encephalopathy, but also symmetric hyperintensities on T2-weighted images in the globus pallidus. Stopping the disulfiram and treating with hydration, high-dose thiamine supplements, and benzodiazepines significantly improved the patient's consciousness and oculomotor function. A magnetic resonance imaging scan after 1 month of treatment showed complete disappearance of the brain lesions and the hyperintensities in the globus pallidus. After a further month of intensive neurorehabilitation, the patient was able to interact with the medical staff, and her neuropsychological tests showed only mild memory impairment. Patients with alcoholism who present at emergency departments are at high risk for misdiagnosis, especially because there is no specific routine laboratory test for detecting asymptomatic disulfiram intoxication. Although uncommon, the combination of Wernicke encephalopathy and disulfiram intoxication should be suspected in patients with alcoholism. The disorder can be detected through a careful history and prompt clinical evaluation, together with characteristic magnetic resonance imaging findings.

Metronidazole-induced Encephalopathy: Case Report and Review Literature.

PURPOSE: Neurotoxicities resulting from various medications are under diagnosed; Metronidazole-induced encephalopathy is one of them. Here we present two patients with a history of metronidazole use and discuss neuroimaging findings. CASE REPORT: We report two patients suffering from acute neurological symptoms associated with metronidazole use. A 70-year-old female who received a cumulative dose of 41.25g of metronidazole within one month, developed seizure. Brain magnetic resonance imaging (MRI) showed T2 hyperintensity over bilateral dentate nuclei and dorsal midbrain. A 56-year-old female suffering from acute onset of central vertigo with metronidazole use, took a total dose of 24g. The brain MRI showed T2 hyperintensity over dorsal midbrain and dorsal medulla, which disappeared in the following neuroimaging 50 days later. Metronidazole-induced encephalopathy (MIE) was suspected in both patients. CONCLUSION: Metronidazole-induced encephalopathy is an uncommon but potentially reversible disease in patients with acute neurological deficits from the use of metronidazole. Nonalcoholic Wernicke's encephalopathy may share a similar metabolic pathway with MIE, resulting in difficulties in diagnosis.

Appraisal of the Glasgow assessment and management of alcohol guideline: a comprehensive alcohol management protocol for use in general hospitals.

BACKGROUND: Guidelines exist for the management of alcohol withdrawal syndrome (AWS) but few have been assessed as to their suitability for general hospitals. The Glasgow Assessment and Management guideline for alcohol has been specifically developed for use in this context. AIM: To determine if this alcohol assessment guideline aids the management of AWS in general hospitals. DESIGN: The four components of the Glasgow Assessment and Management of Alcohol guideline were evaluated. This included the use of the Fast Alcohol Screening Test (FAST) to identify at risk patients, a risk stratification strategy to indicate fixed dose or symptom-triggered benzodiazepine treatment, the Glasgow Modified Alcohol Withdrawal Scale (GMAWS) for symptom-triggered treatment and a clear recommendation for vitamin prophylaxis of Wernicke's encephalopathy. METHODS: FAST scores were assessed along with the CAGE (cut down, annoyed, guilty and eye-opener) screening tool to ascertain if a single screening tool could identify hazardous and dependent drinking. The GMAWS and Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) were compared between two medical units. A staff survey of the two AWS tools was also carried out. RESULTS: FAST was able to identify both probable hazardous and dependent drinking. The GMAWS was reliable and gauged both physical and cognitive aspects of AWS. Staff generally preferred the GMAWS-based treatment as opposed to CIWA-Ar management and welcomed the Guideline as a whole. CONCLUSION: The Glasgow Guideline aids the management of patients with AWS in an acute hospital setting. It allows early identification of at risk patients and directs effective therapeutic intervention.

Clinical features of encephalopathy in children with cancer requiring cranial magnetic resonance imaging.

We analyzed acute neurotoxic problems attributable to chemotherapy or immunosuppression in the context of childhood neoplastic diseases, based on clinical and neuroradiologic findings. This retrospective single-center study reviewed the acute neurologic complications of 62 children receiving conventional chemotherapy or hematopoietic stem cell transplantation from July 2005-July 2008. We excluded patients with central nervous system metastasis and various neurotoxic manifestations not usually requiring cranial magnetic resonance imaging. Of 62 patients, 12 (19.3%) developed acute neurologic complications. The most common complications included posterior reversible encephalopathy syndrome in six of 12 (50%) patients, and Wernicke's encephalopathy in three of 12 (25%) patients. Other complications included chemical arachnoiditis, grey matter injury induced by postchemotherapeutic angiopathy, and leukoencephalopathy. Posterior reversible encephalopathy syndrome was accompanied by hypertensive episodes in most patients (5/6), and Wernicke's encephalopathy was evident with altered mental status in malnourished children. These data indicate that posterior reversible encephalopathy syndrome and Wernicke's encephalopathy are the predominant complications in children undergoing chemotherapy or hematopoietic stem cell transplantation. Early radiologic and clinical evaluation and prompt treatment for these complications are necessary to prevent their progression to irreversible brain damage.

Clinical and pathological features of alcohol-related brain damage.

One of the sequelae of chronic alcohol abuse is malnutrition. Importantly, a deficiency in thiamine (vitamin B(1)) can result in the acute, potentially reversible neurological disorder Wernicke encephalopathy (WE). When WE is recognized, thiamine treatment can elicit a rapid clinical recovery. If WE is left untreated, however, patients can develop Korsakoff syndrome (KS), a severe neurological disorder characterized by anterograde amnesia. Alcohol-related brain damage (ARBD) describes the effects of chronic alcohol consumption on human brain structure and function in the absence of more discrete and well-characterized neurological concomitants of alcoholism such as WE and KS. Through knowledge of both the well-described changes in brain structure and function that are evident in alcohol-related disorders such as WE and KS and the clinical outcomes associated with these changes, researchers have begun to gain a better understanding of ARBD. This Review examines ARBD from the perspective of WE and KS, exploring the clinical presentations, postmortem brain pathology, in vivo MRI findings and potential molecular mechanisms associated with these conditions. An awareness of the consequences of chronic alcohol consumption on human behavior and brain structure can enable clinicians to improve detection and treatment of ARBD.

Timing of efficacy of thiamine in Wernicke's disease in alcoholics at risk.

This study investigated an optimum window of effectiveness of oral thiamine in alcohol withdrawal in a jail setting using a Librium-based protocol. A total of 19 patients were identified with alcohol withdrawal at intake. Clinical Institute Withdrawal Assessment (CIWA-AR), Cut back, Annoyed, Guilty, Eye-opener (CAGE) questionnaire, and therapy were started immediately. Of these patients, 9 were identified as high risk and 2 developed an excited delirium consistent with Wernicke's disease. This study demonstrated an optimum window of 2 hours or less at intake with oral thiamine. The earlier an oral withdrawal protocol is started, the faster is recovery, regardless of initial presentation. Disease progression was significantly dependent on time to treat. Noncompliance with oral management is likely if treatment is delayed. The routine use of thiamine 100 mg daily during withdrawal and continuation for 30 days is recommended as the best clinical practice.