Magnetization Transfer Imaging Provides No Evidence of Demyelination in Methotrexate-Induced Encephalopathy

Abstract

SUMMARY: Subacute MTX-induced encephalopathy is characterized by an abrupt onset of focal neurologic deficits within days after intrathecal or systemic therapy. Demyelination is one proposed mechanism. We describe the neuroimaging features of 2 patients with clinical symptoms of subacute encephalopathy after intrathecal and systemic MTX therapy. DWI showed restricted diffusion, indicating cytotoxic edema. MTI yielded no evidence of demyelination in either patient because there was no loss of MTR in areas of restricted diffusion.ABBREVIATIONS: ADC ϭ apparent diffusion coefficient; ALL ϭ acute lymphoblastic leukemia; DWI ϭ diffusion-weighted imaging; IT ϭ intrathecal; IV ϭ intravenous; MTI ϭ magnetization transfer imaging; MTR ϭ magnetization transfer ratio; MTX ϭ methotrexate I n the prophylaxis of central nervous system leukemia, IT MTX has largely replaced cranial irradiation and has lead to improved survival outcomes.1 Toxic effects of MTX include mucositis, myelosuppression, nephrotoxicity, hepatotoxicity, and neurotoxicity with acute (within hours), subacute (days to weeks after administration), and chronic (after months and years) encephalopathy. 2Subacute MTX-induced encephalopathy is characterized by a delayed onset of strokelike symptoms, such as aphasia, hemiparesis, and ataxia. Complete resolution of symptoms after therapy is usually seen in patients with encephalopathy. The pathophysiology of MTX-induced encephalopathy is incompletely understood. Demyelination and adenosine release have been proposed to contribute to the development of the disease. [3][4][5] DWI has been used to diagnose cytotoxic edema in subacute MTX-induced encephalopathy 6 but does not assess demyelination. MTI is a diagnostic tool known to be sensitive to demyelination. 7 We report on 2 cases of subacute MTX-induced encephalopathy following IT MTX therapy in pediatric patients with ALL, who presented with typical neuroimaging without signs of demyelination on MTI. Case ReportsPatient 1, a 13-year-old girl with biphenotypic ALL, received chemotherapy according to the COALL-07-03 protocol (high-risk standard).8 Twelve days after the third treatment with 12 mg of IT MTX, she developed prickling sensations and a central facial nerve paresis on the right side. Conventional MR imaging showed changes on T2-weighted imaging with faint hyperintensity of the white matter in both hemispheres. DWI hyperintensity and low ADC were observed in the centrum semiovale of both hemispheres, corresponding to restricted diffusion.MTI used two 2D gradient-echo sequences. The first acquisition had no saturation pulse. The second used a saturation pulse 1.2 kHz below H 2 O frequency. The MTR is the percentage of signal-intensity loss induced: MTR ϭ (S 0 Ϫ S s ) / S 0 ϫ 100%, where S 0 is the signal intensity of a pixel obtained from the sequence without the saturation pulse and S S is the signal intensity with the saturation pulse.MTR maps showed symmetric values of the white matter, and there was no loss of MTR in areas of DWI or T2 hyperintensity (Fig ...

Etiologies, Cerebral Vasomotion, and Endothelial Dysfunction in the Pathophysiology of Posterior Reversible Encephalopathy Syndrome in Pediatric Patients

“…Common culprit xenobiotics causing endothelial dysfunction and consequently precipitating PRES in pediatric patients with hematologic disease include cytarabine, a cell-cycle active purine analogue utilized in the treatment of acute myelogenous leukemia, methotrexate, a dihydrofolate reductase inhibitor utilized in the maintenance and consolidation therapy of ALL, and L-asparaginase, an enzyme degrading the essential amino acid L-asparagine, utilized in the induction regimen of ALL. 19,238 The chemotherapeutic enzyme L-asparaginase, utilized to deplete rapidly dividing cancer cells of the essential amino acid L-asparagine, appears to be a powerful risk factor significantly amplifying the risk of developing PRES in patients undergoing treatment of various malignancies, 20,48,157,[239][240][241] though it may alternatively cause iatrogenic encephalopathies distinct from the PRES proper, a property shared by methotrexate (e.g., diffuse necrotizing leukoencephalopathy and mineralizing microangiopathy). [242][243][244] Interference with the hepatic synthesis of procoagulant and anticoagulant proteins may possibly generate thromboembolic and/or hemorrhagic consequences 245,246 and could contribute to mediating the cerebrovascular dysautoregulation necessary to generate PRES.…”

Pengaruh Pemberian Vitamin B6 dan Vitamin B12 Terhadap Konsentrasi Homosistein Serum pada Pasien Leukemia Limfoblastik Akut

“…Konsentrasi homosistein 11,1 µmol/L memiliki lobus temporal medial 24,5% mengalami penipisan setelah 3 tahun bila dibandingkan dengan konsentrasi homositein <11,1 µmol/L. 17 Penelitian di Framingham, melaporkan konsentrasi plasma homosistein 14 µmol/L memiliki risiko 2 kali untuk terjadinya demensia. Risiko demensia meningkat 40% untuk setiap 5 mmol/L kenaikan homosistein plasma.…”

Neurologische Komplikationen antirheumatischer Pharmakotherapeutika

“…Akut innerhalb von Stunden, subakut oder chronisch nach monate-oder jahrelanger Therapie kann sich eine sog. MTX-Enzephalopathie entwickeln [72]. Die akute Form äußert sich durch Kopfschmerzen, Übelkeit, Erbrechen, Lethargie, psychische Veränderungen, Sehstörungen, fokale zentralnervöse Ausfälle und epileptische Anfälle [73], die subakute durch eventuell schlaganfallähnlich auftretende zentralnervöse Defizite wie Aphasie, Hemiparese, Bewegungs-oder Schluckstörungen oder auch Verwirrtheit [72], die chronische durch langsam fortschreitende neurologische Defizite [73].…”

“…1-3 % [72,73], die bei Karzinomtherapie 3-15 % [73]. Nur selten tritt sie nach längerdauernder niedrigdosierter oraler Applikation auf [7,8,[72][73][74]. Nach Absetzen der Medikation ist eine Rückbildung möglich, Todesfälle sind jedoch beschrieben worden [8].…”

“…Die exakte Pathogenese ist bisher nicht gesichert, eine zuverlässige Therapie existiert bisher nicht [73,74]. Computertomografisch findet man Marklagerhypodensitäten [7], magnetresonanztomografisch typischerweise eine Diffusionsrestriktion und eventuell Hyperintensitäten auf den T2-und Flair-gewichteten Sequenzen im tiefen zerebralen Marklager [8,14,72,73,[75][76][77]. Risikofaktoren sind die kumulative systemische Dosis, hohe Methotrexat : Leukovorin-Quotienten, eine kombinierte intravenöse und intrathekale Gabe, ein Alter über 10 Jahren und vermutlich eine frühere Behandlung [74].…”