Methotrexate-induced neurotoxicity (MTX-Ntox) is a frequent complication of methotrexate (MTX) therapy for patients with both malignant and inflammatory diseases. MTX-Ntox can occur after intrathecal MTX or after low-, intermediate-, or high-dose systemic administration. Symptoms can present in the acute, subacute, or late setting form, and can range from affective disorders, malaise, and headaches, to somnolence, focal neurologic deficits, and seizures. While the pathogenesis of MTX-Ntox is likely multifactorial, one potential biochemical pathway leading from MTX to neurotoxicity involves the folate dependent remethylation of homocysteine (Hcy). MTX therapy is known to cause elevations of both plasma and CSF Hcy. Hcy is directly toxic to vascular endothelium and it and its metabolites are excitatory agonists of the N-methyl-D-aspartate (NMDA) receptor. Competitive or noncompetitive antagonists might afford protection from or reversal of MTX-Ntox. Using high-performance liquid chromatography (HPLC) with coulometric electrochemical detection, the authors measured CSF Hcy in sequential patients with severe subacute MTX-Ntox. CSF Hcy was higher in these patients (n = 9, median = 0.93 microM) than in asymptomatic patients (n = 11, median 0.2 microM, p < .01). Five patients with severe subacute MTX-Ntox (most with dysarthria and/or hemiplegia) were treated with 1-2 mg/kg oral dextromethorphan (DM), a noncompetitive antagonist of the N-methyl-1-aspartate (NMDA) receptor. All five had resolution of symptoms. These data provide additional clinical support for elevated CSF Hcy in the induction of MTX-Ntox through activation of the NMDA-receptor. These data provide support for a placebo-controlled clinical trial to examine the ability of DM to prevent or alleviate MTX-Ntox.

Higher doses of LMWH are required in the preterm infant as compared with the healthy term neonate. Once therapeutic levels are achieved, continued regular monitoring and dose adjustments are required to maintain anticoagulation in therapeutic range.

National Institutes of Health and the St. Baldrick's Foundation.

Dextromethorphan (DM) is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, which is widely used as an antitussive agent. DM also prevents neuronal damage and modulates pain sensation via noncompetitive antagonism of excitatory amino acids (EAAs). DM has been found to be useful in the treatment of pain in cancer patients and in the treatment of methotrexate-induced neurotoxicity. Clinical studies with DM in cancer patients are reviewed in this article.

Cerebrovascular disease is a common cause of morbidity in sickle cell anemia (HbSS): approximately 10% of patients have a clinical stroke before 20 years of age, and another 22% have silent infarction on magnetic resonance imaging. The phenotypic variation among patients with HbSS suggests a role for modifier genes and/or environmental influences. To assess the familial component of clinical stroke in HbSS, we estimated the prevalence of clinical stroke among all patients and among HbSS sibling pairs at 9 pediatric centers. The sample included 3425 patients with sickle cell disease who were younger than 21 years, including 2353 patients with HbSS. The stroke prevalence was 4.9% for all genotypes; 7.1% for patients with HbSS; 1.1% for patients with HbS␤ o thalassemia; 0.6% for patients with S␤ ؉ thalassemia; and 0% for patients with HbSC. In 207 sibships, more than 1 child had HbSS. There were 42 sibships in which at least 1 sibling had a stroke, and in 10 of the 42, 2 siblings had a stroke. A permutation test indicated that the number of families in which 2 children had strokes was larger than the number expected if strokes were randomly distributed among children in sibships (P ‫؍‬ .0012). There was no difference in stroke prevalence based on sex, nor was the mean age at stroke presentation significantly different between singletons and sibships with stroke. We conclude that there is a familial predisposition to stroke in HbSS. Attempts to identify genetic modifiers should be initiated with familybased studies. IntroductionCerebrovascular disease is the second leading cause of mortality and a common cause of morbidity in sickle cell anemia (HbSS): approximately 10% of patients will have a clinical stroke by age 20 years, and another 22% have evidence of silent infarction on magnetic resonance imaging (MRI). 1,2 The pathophysiology of cerebrovascular disease in sickle cell anemia may involve stenosis of large arteries of the circle of Willis, intracranial hemorrhage, and/or microvascular disease. 3,4 The histology of these vascular lesions demonstrates intimal hyperplasia and smooth muscle proliferation compatible with endothelial damage. 5 A moyamoya pattern of lenticulostriate collateral vessels develops around the areas of stenosis in about 30% of patients. 6 Patients with moyamoya also have a higher risk for recurrent stroke. 7 Features of sickle cell disease that predispose patients to endothelial damage include adhesive properties of sickle reticulocytes (promoted by adhesion proteins, von Willebrand factor, and thrombospondin), leukocyte adhesion, and biomechanical disturbances of fluid shear stresses generated by increased blood flow secondary to anemia. [8][9][10] The propensity for stroke is associated with abnormal blood flow velocity in large arteries that can be detected presymptomatically by transcranial Doppler (TCD). 11 A familial predisposition to stroke in sickle cell anemia has been suggested by the observation that the prevalence of stroke among siblings with HbSS appears to be increased. 12...