Endothelial Dysfunction and Hyperhomocysteinemia-Linked Cerebral Small Vessel Disease: Underlying Mechanisms and Treatment Timing

Cerebral small vessel disease (cSVD)—a common cause of stroke and vascular dementia—is a group of clinical syndromes that affects the brain's small vessels, including arterioles, capillaries, and venules. Its pathogenesis is not fully understood, and effective treatments are limited. Increasing evidence indicates that an elevated total serum homocysteine level is directly and indirectly associated with cSVD, and endothelial dysfunction plays an active role in this association. Hyperhomocysteinemia affects endothelial function through oxidative stress, inflammatory pathways, and epigenetic alterations at an early stage, even before the onset of small vessel injuries and the disease. Therefore, hyperhomocysteinemia is potentially an important therapeutic target for cSVD. However, decreasing the homocysteine level is not sufficiently effective, possibly due to delayed treatment, which underlying reason remains unclear. In this review, we examined endothelial dysfunction to understand the close relationship between hyperhomocysteinemia and cSVD and identify the optimal timing for the therapy.

Methotrexate(MTX) Induced Leukoencephalopathy(LE) and Relation of Vitamin B12, Folate and / or Homocysteine Levels with MTX Toxicity: A Prospective Study

Background: MTX-induced neurotoxicity is often associated with leukoencephalopathy, and the diagnostic radiological feature in magnetic resonance imaging (MRI) is white matter hyper intensities. The clinical significance of these white matter changes is unknown. The risk factors of MTX-induced acute leukoencephalopathy are not well established. Few authors have suggested increased homocysteine or alteration of Central Nervous System (CNS) folate, vitamin b12 homeostasis may be associated with CNS toxicity. It is a usual clinical practice to withhold methotrexate during further duration of chemotherapy after an episode of leukoencephalopathy but the risk of neurotoxicity must be weighed against the risk of relapse of leukemia. Moreover, there is limited data on continued treatment with High-dose methotrexate (HD-MTX) or Intrathecal Methotrexate (IT-MTX) or Oral-MTX in patients who developed leukoencephalopathy. Objective: The study aims to 1) identify the risk and prevalence of leukoencephalopathy in patients of Acute Lymphoblastic Leukemia (ALL) receiving intrathecal or high dose or oral methotrexate therapy through sequential MRI Brain study. 2) Safety of re-administration of methotrexate in patients with documented toxic leukoencephalopathy 3) The relationship of serum homocysteine, vitamin b12 and folate levels with methotrexate induced leukoencephalopathy Methods: Our study enrolled 34 newly diagnosed pediatric ALL / Lymphoblastic Lymphoma (LBL) patients (age ≤18 years) between June 2019 & June 2020. Induction chemotherapy was initiated as per modified ALL IC BFM 2002 protocol after obtaining informed consent. Apart from the Hematological investigations, Bone Marrow Aspiration and Biopsy, Flow Cytometry/Immunohistochemistry (IHC), Cytogenetics, Molecular study were done. All the patients underwent MRI Brain and Serum homocysteine, Vitamin B12, Folate level measurement (sequentially as per protocol at 4 different time points). 1st time point - AT DIAGNOSIS, i.e. before starting methotrexate, 2nd time point - POST CONSOLIDATION, 3rd time point - POST EXTRACOMPARTMENT THERAPY, 4th time point - IN MAINTENANCE, thus analyzing leukoencephalopathy secondary to different modes of administration of methotrexate therapy. At all-time points serum folate, vitamin b12 or homocysteine level were done before administering methotrexate and any association with development of leukoencephalopathy was analyzed. Results: We identified Leukoencephalopathy secondary to methotrexate in 6.03% (7/116) on MRI brain in 5 of 33 (15.15%) patients of which 1 (3.03%) had symptomatic LE and 4 (12.12%) were clinically asymptomatic. All our LE patients were in the age group more than or equal to 10 years. We found no increase in the incidence of leukoencephalopathy secondary to methotrexate: leucovorin ratio, also there was no difference in the incidence with respect to mode of administration of MTX (IT/HD/ORAL), even there was no increase in incidence after 4 courses of high dose methotrexate. MRI at baseline was not a predictor of development of leukoencephalopathy. 3 out of 5 patients with LE had abnormal b12/folate/homocysteine with corresponding abnormal MRI Brain at pre-specified time point. Also 4 patients with abnormal b12/folate/homocysteine levels had intractable cytopenias while on chemotherapy and more after HD MTX therapy which got corrected after supplementation with vitamin b12 and folic acid. Conclusion: MTX-induced clinical leukoencephalopathy is transient, and most patients can be re-challenged with subsequent MTX without recurrence of acute or subacute symptoms. MRI at baseline was not a predictor of development of leukoencephalopathy. More multi institutional prospective studies of large number of patients are needed to study the incidence of MTX-induced leukoencephalopathy and its relation with folic acid, vitamin b12 and homocysteine level. Disclosures No relevant conflicts of interest to declare.

ANALYSIS AND CORELATION OF A PANEL OF SERUM BIOMARKERS WITH TREATMENT OUTCOME OF ISCHEMIC HEART DISEASE IN A TERTIARY CARE HOSPITAL OF WEST BENGAL

Background :In India Ischemic heart disease (IHD ) is the of most common causes of mortality and morbidity . Several studies have pointed out a strong association of serum Lipoprotein (a) , Homocysteine and highly sensitive – C reactive protein [hs-CRP],with IHD , but these markers have been studied in isolation . Aim: The aim of the study was to assess diagnostic potential of the above biomarkers as well as their ability to reect treatment outcome. Results : The results of statistical analysis showed that levels of serum Lp (a) and serum homocysteine were signicantly raised in patients in of IHD compared to their apparently age and sex matched controls whereas the level of serum hsCRP level did not showed any signicant difference in between cases and controls. We also found signicant lower value of serum level Lp (a), homocysteine and hsCRP in 3 months and 6 months post treated cases compared to untreated cases of IHD. But failed to show any signicant correlation in between serum levels of Lp(a) , hsCRP and Homocysteine level with disease severity( LVEF%) of IHD. Conclusion :So the serum Lp(a) , hsCRP and Homocysteine level is associated with increase risk factor of IHD and would be a better upcoming diagnostic and marker for diagnosis of IHD patients .

Homocysteine as a Predictor Tool in Multiple Sclerosis

Multiple sclerosis (MS) is a progressive and irreversible disease which affects the central nervous system (CNS) with still unknown etiology. Our study aimes to establish the homocysteine pattern that can predict the MS diseases progression and to identify a potential disease progression marker that can be easy to perform and non-invasive, in order to predict the diseases outcome. In order to achieve this goal, we included 10 adult RRMS subjects, 10 adult SPMS subjects and 10 age-matched healthy subjects. The homocysteine plasma level was measured using automated latex enhanced immunoassay and the cobalamin and folate measurements were performed using automated chemiluminescence immunoassay (CLIA). HCR was calculated by dividing the homocysteine plasma level by cobalamin plasma level. We found that the homocysteine level in plasma of both RRMS patients and SPMS group are significantly increased compared with the control group. There is a significantly higher concentration of homocysteine in SPMS group compared with the RRMS group. In addition, the HCR is significantly increased in SPMS compared with the RRMS group and is a very good index of disease severity.

Clinical Utility of Serum Holotranscobalamin Measurements in Patients with First-Ever Ischemic Stroke

Background. Whether holotranscobalamin (holoTC) indicates B12 deficiency more sensitively than total vitamin B12 (B12) is unclear. This study is aimed at determining the impact of serum holoTC level as a risk factor for ischemic stroke and investigating its association with disease severity and short-term outcomes. Methods. Serum holoTC, total B12, and homocysteine levels were compared between 130 stroke patients and 138 healthy controls. Biomarker level correlations with disease severity and stroke functional outcomes were investigated. Results. holoTC levels were lower and homocysteine levels were higher in stroke patients than in healthy controls ( P < 0.05 ). The holoTC/total B12 ratio and homocysteine level significantly predicted ischemic stroke in the multivariable regression analysis ( P < 0.05 ). Along with hyperhomocysteinemia, patients more often had holoTC than total B12 deficiency (6.2% vs. 3.1%). holoTC levels negatively correlated with homocysteine levels (partial R -0.165, P < 0.05 ) in stroke patients in multiple linear regression analyses, but not total B12 levels. The holoTC level and holoTC/total B12 ratio, but not homocysteine and total B12 levels, negatively correlated with the National Institute of Health Stroke Scale (partial R , -0.405 and -0.207, respectively, P < 0.01 ). Conclusions. Measurements of serum holoTC levels combined with total B12 and homocysteine levels may provide valuable information for predicting ischemic stroke and its severity and short-term outcomes of ischemic stroke patients.

Extensive Cerebral Venous Thrombosis Secondary to Recreational Nitrous Oxide Abuse

Nitrous oxide, colloquially known as “whippets,” is a commonly abused inhalant by adolescents and young adults. There are limited data describing the adverse effects of this abuse. We present a 16-year-old girl with no medical history who presented to the emergency department for confusion, hallucinations, weakness, and headaches. Imaging revealed extensive cerebral thrombosis. She had no prior history of venous or arterial thrombosis. Hypercoagulability workup demonstrated an elevated homocysteine level. She was treated with effective anticoagulation and vitamin B12 folate supplementation. To our knowledge, there are a very few cases in the medical literature of cerebral venous thrombosis following the use of nitrous oxide. The pathophysiology of the disorder appears to be linked to the metabolism of vitamin B12 inducing hyperhomocysteinemia and a procoagulant state.