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.

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.

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.

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.

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.

The Korsakoff syndrome: clinical aspects, psychology and treatment.

AIMS: The Korsakoff syndrome is a preventable memory disorder that usually emerges (although not always) in the aftermath of an episode of Wernicke's encephalopathy. The present paper reviews the clinical and scientific literature on this disorder. METHODS: A systematic review of the clinical and scientific literature on Wernicke's encephalopathy and the alcoholic Korsakoff syndrome. RESULTS: The Korsakoff syndrome is most commonly associated with chronic alcohol misuse, and some heavy drinkers may have a genetic predisposition to developing the syndrome. The characteristic neuropathology includes neuronal loss, micro-haemorrhages and gliosis in the paraventricular and peri-aqueductal grey matter. Lesions in the mammillary bodies, the mammillo-thalamic tract and the anterior thalamus may be more important to memory dysfunction than lesions in the medial dorsal nucleus of the thalamus. Episodic memory is severely affected in the Korsakoff syndrome, and the learning of new semantic memories is variably affected. 'Implicit' aspects of memory are preserved. These patients are often first encountered in general hospital settings where they can occupy acute medical beds for lengthy periods. Abstinence is the cornerstone of any rehabilitation programme. Korsakoff patients are capable of new learning, particularly if they live in a calm and well-structured environment and if new information is cued. There are few long-term follow-up studies, but these patients are reported to have a normal life expectancy if they remain abstinent from alcohol. CONCLUSIONS: Although we now have substantial knowledge about the nature of this disorder, scientific questions (e.g. regarding the underlying genetics) remain. More particularly, there is a dearth of appropriate long-term care facilities for these patients, given that empirical research has shown that good practice has beneficial effects.

A case of Wernicke's encephalopathy following fluorouracil-based chemotherapy.

The pyrimidine antimetabolite 5-fluorouracil (5-FU) is a chemotherapeutic agent used widely for various tumors. Common side effects of 5-FU are related to its effects on the bone marrow and gastrointestinal epithelium. Neurotoxicity caused by 5-FU is uncommon, although acute and delayed forms have been reported. Wernicke's encephalopathy is an acute, neuropsychiatric syndrome resulting from thiamine deficiency, and has significant morbidity and mortality. Central nervous system neurotoxicity such as Wernicke's encephalopathy following chemotherapy with 5-FU has been reported rarely, although it has been suggested that 5-FU can produce adverse neurological effects by causing thiamine deficiency. We report a patient with Wernicke's encephalopathy, reversible with thiamine therapy, associated with 5-FU-based chemotherapy.

Sudden bilateral blindness in Wernicke's encephalopathy: case report and review of the literature.

We report on a patient suffering from bilateral sudden blindness as initial symptom of Wernicke's encephalopathy (WE). A 37-year-old male alcoholic was admitted to a psychiatric clinic because of excessive alcohol consumption (3.4 per thousand). 24 h later he developed acute bilateral blindness with no light perception, downbeat nystagmus, bilateral ocular abduction deficits, cerebellar ataxia as well as a slight psychomotor slowing and mild disorientation. MRI including diffusion-weighted imaging and MR-angiography 3 h after symptom onset did not reveal findings suggestive for ischemic stroke. Immediate iv-application of thiamine led to a nearly complete remission of the neuroophthalmologic symptoms within 12 h. Although we critically discuss other potential etiologies, we conclude that the complex clinical picture with initial sudden blindness is an unusual presentation of WE.

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.

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.

[Unusual cortical compromise in a case of Wernicke's encephalopathy]. / Afectación cortical inusual en un caso de encefalopatía de Wernicke.

INTRODUCTION: Wernicke's encephalopathy (WE) is a metabolic disease due to thiamine deficiency; only 10% of cases are diagnosed pre-mortem. Symptoms of WE include ophthalmoplegia, nistagmus, ataxia and mental confusion; post-mortem examination shows characteristic symmetrical lesions in the mamillary bodies (MB), hypothalamus, thalamus, brain stem and cerebellum with spongiosis, demyelination, vascular proliferation and relative preservation of neurons. CASE REPORT: 50 years-old male with alcoholic hepatopathy and orthotopic hepatic transplant who suffered a second surgical intervention 10 days after due to problems in the biliar anastomosis. After this second surgery he showed an altered mental status, with fluctuating global confusion, disorientation and agitation. He died 52 days after the hepatic transplantation. Autopsy study showed bilateral broncopneumonia, brown discoloration of the MB and bilateral linear lesions in the cortex of both motor gyri, which histologically showed identical to the MB lesions with demyelination, capillary and glial proliferation and preservation of neurons. Alzheimer type II astrocytes were also found in basal nuclei and cortex. CONCLUSIONS: Typical WE lesions affect MB, hypothalamus, thalamus, brain stem and cerebellum; cortical lesions, when found, are due to hepatocerebral degeneration with Alzheimer type II astrocytes or to the citopathic effects of ethanol. In our case, cortical lesions were identical to the lesions found in MB, an extraordinary finding which we have not found reported in the literature.

[Iatrogenic neurological disorders in old people: a review].

Aged people are frequently the victims of iatrogenic diseases, especially adverse effects of drugs since they are affected by many age-related diseases and are given many drugs. Geriatric medicine in Japan has a bitter history of having produced many victims by adverse effects of cerebral vasodilators and cerebral stimulants; they included parkinsonism and depression induced by flunarizine and cinnarizine, and Reye-like encephalopathy induced by calcium hopantenate. Parkinsonism induced by sulpiride, tiapride, metoclopramide or atypical anti-psychotics, dyskinesia induced by anti-parkinsonian drugs or anti-psychotics, and psychotic symptoms induced by anti-parkinsonian drugs, anti-cholinergic drugs, anti-depressants or histamine H2 antagonists are still very common. Wernicke encephalopathy caused by intravenous glucose infusion without thiamine, central pontine myelinolysis by too rapid correction of hyponatremia are important though infrequent. Iatrogenic Creutzfeldt-Jakob disease by dura grafts is a warning against the easy use of medical materials produced with human organs or blood. Iatrogenic diseases are preventable, and geriatricians have to pay attention to the information on adverse effects of drugs and medical materials and carefully observe the early signs of iatrogenic diseases.

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.

Transketolase abnormality in tolazamide-induced Wernicke's encephalopathy.

We studied a thiamine-dependent enzyme, transketolase, from fibroblasts of a diabetic patient who developed Wernicke's encephalopathy when treated with tolazamide, in order to delineate if this patient also had transketolase abnormality [high Km for thiamine pyrophosphate (TPP)], as previously reported in postalcoholic Wernicke-Korsakoff syndrome. In addition to this patient, we also studied this enzyme from three diabetic kindreds without any history of Wernicke's encephalopathy and from four normal controls. We found that the above-mentioned patient and one of the diabetic kindreds with no history of Wernicke's encephalopathy had abnormal transketolase as determined by its Km for TPP. These data suggest a similarity between postalcoholic Wernicke-Korsakoff syndrome and the patient with tolazamide-induced Wernicke's encephalopathy from the standpoint of transketolase abnormality.

Radio-frequency lesions of the thalamus produce delayed-nonmatching-to-sample impairments comparable to pyrithiamine-induced encephalopathy in rats.

Rats were trained and matched on a delayed-nonmatching-to-sample (DNMTS) task and randomly assigned to treatment. In Experiment 1, radio-frequency (RF) lesions were aimed at lateral portions of the internal medullary lamina (L-IML), midline thalamus (MT), mammillary bodies (MB), and the combination of MT and MB. In Experiment 2, RF lesions were aimed at the fornix. After recovery, DNMTS was retrained at retention intervals retention interval of 3.0-18.0 s, the critical retention interval for 75% DNMTS accuracy was determined by a staircase procedure, and spontaneous exploration was observed in an open field. L-IML lesions produced significant deficits on DNMTS and exploratory behavior that were comparable to deficits on the same tasks in rats recovered from pyrithiamine-induced thiamine deficiency. Fornix lesions produced significant DNMTS deficits that were substantially smaller than for the L-IML group. The MT, MB, and MT+MB treatments had no significant effect on DNMTS.