Figure - available from: Frontiers in Neurology
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MRI of Patient 6, showing hyperintensity of the deep white matter on T2-weighted images and signs of cytotoxic oedema in DWI.
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Introduction
Stroke-like syndrome (SLS) is a rare subacute neurological complication of intrathecal or high-dose (≥500 mg) Methotrexate (MTX) administration. Its clinical features, evoking acute cerebral ischaemia with fluctuating course symptoms and a possible spontaneous resolution, have elicited interest among the scientific community. However,...
Citations
... A repertoire of pharmacotherapeutic agents including corticosteroids, azathioprine, cyclophosphamide, methotrexate, and TNFα antagonists have been adopted for addressing pNBD [49]. Interestingly, methotrexate has been involved in forms of neurotoxicity, although such manifestations mainly occur in case of high doses and intrathecal administration [53]. Corticosteroids are administered in cases with dural sinus thrombosis, whereas anti-TNF agents may be contemplated in patients with recurrent forms or in cases of arterial involvement [49]. ...
Citation: Santangelo, A.; Corsello, A.; Gizzi, G.; Lancieri, M.; Diana, M.C.; Trucco, F.; Orsini, A.; Bonuccelli, A.; Peroni, D.G.; Perilli, L.; et al. Exploring Headaches in Pediatric Behçet Disease: Prevalence, Clinical Impact, and Management. J. Clin. Med. 2024, 13, 3659. https://doi. Abstract: Behçet's Disease (BD), also recognized as Behçet Syndrome, manifests uniquely in pedi-atric populations as Pediatric Behçet's Disease (PBD), characterized by multisystemic inflammatory symptoms including recurrent oral and genital aphthae, and diverse ocular, vascular, and neuro-logical involvements. This review elucidates the prevalence, burden, and management strategies of headaches in children with PBD, focusing on both primary headaches, such as migraine and tension-type headaches, and secondary headaches linked to systemic disease manifestations. It explores the pathophysiological underpinnings specific to PBD-related headaches and discusses the intricate relationship between systemic inflammatory processes and neurological symptoms. By examining the literature from 2004 to 2024, this study highlights the high frequency of headache in PBD patients, underscoring its diagnostic and clinical significance. We aim to provide a detailed understanding of headache management in PBD, emphasizing tailored therapeutic strategies that address the unique challenges faced by this patient population. This review also underscores the importance of comprehensive clinical evaluations to optimize outcomes and mitigate long-term sequelae, proposing that awareness and understanding of headache in PBD can significantly enhance both diagnosis and management.
... [3][4][5] Methotrexate-induced neurotoxicity may vary depending upon the dose, frequency, route of administration, patient age, race and ethnicity. [6][7][8] Direct toxic increase in homocysteine, decrease in S-adenosyl methionine (SAM) and increase in excitatory amino acids are some of the postulated mechanisms of this neurotoxicity. 8 Risk factors attributed to MTX-induced neurotoxicity include adolescent age, high-risk ALL therapy, elevated aspartate aminotransferase during ALL induction/consolidation cycles and high serum creatinine. ...
... High-risk (HR) arm was administered to T-cell phenotype, B-cell ALL with NCI high risk, significant organomegaly (liver or spleen ≥5 cm below the costal margin irrespective of age and weight), testicular involvement and CNS leukaemic involvement (CNS2/3) at presentation, t (1,19), poor prednisolone response, end induction bone marrow flow-cytometric minimal residual disease (BM-MRD) positivity (≥0.01%), mixed phenotypic acute leukaemia (MPAL) and LBL (irrespective of stage), who received HDMtx at 5 g/ m 2 as intravenous infusion over 24 h along with hydration, alkalinisation and injection folinic acid (15 mg/m 2 ) rescue beginning at 42 h after the start of HDMtx, continued every 6th hourly till serum MTX < 0.3 μmol/L during interim maintenance (protocol M). Very high-risk (VHR) arm of the protocol was given to B-ALL patients who were Philadelphia positive, Hypodiploid (Chr≤44), IAMP21, t (17,19), MLL rearrangement, induction failure and post-consolidation BM-MRD positivity (≥0.01%) with high-risk blocks (3)(4)(5)(6) containing HDMtx at 5 g/m 2 as 24-h infusion with injection folinic acid rescue as described earlier. Serum MTX levels were assessed using Emit® Methotrexate assay kit based on homogenous enzyme immunoassay technique. ...
... Reported incidence of methotrexate-induced neurotoxicity in childhood ALL ranges between 3% and 7%. 6 In a recent multicentre study on 1251 ALL children by Mateos et al., 7.6% of patients had MTX-induced neurotoxicity. 9 Our study almost had a similar incidence rate of 6.9%. ...
Methotrexate (MTX), although an indispensable part of contemporary treatment protocols for childhood acute lymphoblastic leukaemia (ALL)/lymphomas (LBL) in improving outcomes, can lead to serious neurotoxicity with long‐term consequences. The aetiopathogenesis, predisposing factors and treatment for MTX‐induced neurotoxicity are not yet well defined. The aim of our study was to detect the incidence, risk factors and to assess the overall outcomes of MTX‐induced neurotoxicity among large cohort of paediatric ALL/LBL patients treated on a uniform protocol. We conducted retrospective audit of medical records of 622 consecutive children (≤14 years) diagnosed with ALL and LBL between January 2018 and December 2022 and treated on modified BFM‐95 protocol at the Department of Pediatric Oncology, Regional Cancer Centre, Thiruvananthapuram. Risk factors predisposing to MTX‐induced neurotoxicity were identified using binary logistic regression analysis. Forty‐three children were diagnosed with MTX‐induced neurotoxicity with an incidence rate of 6.9%. More than two‐thirds of them had high‐grade MTX‐induced neurotoxicity CTCAE v5.0 with a median age of 9 years (range: 9 months to 14 years). Almost half of them developed MTX neurotoxicity during Protocol M followed by Phase‐Ib consolidation (15%). Majority of these patients (84%, 36/43) were challenged again with MTX, with 11% (4/36) developing recurrence. Fifteen per cent had persistent neurological deficits at last follow‐up. Univariate analysis found older age (age > 5 years) (p < 0.001), T‐cell phenotype (p = 0.040), tumour lysis syndrome during induction (p < 0.001), baseline renal problems prior to MTX exposure (p < 0.001) and CNS leukaemic involvement (p < 0.003) to be significantly associated with MTX neurotoxicity. On multivariate analysis, older age (>5 years), tumour lysis during induction and CNS leukaemia retained statistical significance (p < 0.05). Methotrexate‐induced neurotoxicity during paediatric acute lymphoblastic leukaemia/lymphoma therapy is a transient phenomenon in majority and re‐challenge with MTX is generally safe. Older age children who develop tumour lysis during induction and CNS leukaemic involvement are at increased risk for MTX‐induced neurotoxicity during ALL/LBL treatment.
Methotrexate-induced neurotoxicity is a well-defined side-effect of high-dose and intrathecal methotrexate with characteristic clinico-radiological findings and transient nature. Our experience in managing this entity in children with acute lymphoblastic leukemia(ALL) is reported here. All children with de novo ALLregistered from January 2016 through December 2021 who developed methotrexate-induced neurotoxicity were included. Of children with ALL treated during the study period, thirty-three experienced methotrexate induced neurotoxicity with an incidence of 1.25%. Stroke-like symptoms(36.36%; 12/33) were the most common clinical manifestation followed by seizures(30.3%, 10/33). Twenty-three patients had radiological features consistent with methotrexate-induced leukoencephalopathy. With emerging evidence, thirty-one patients were re-challenged with methotrexate (IV/IT), of whom 4 patients had recurrence of symptoms. No long-term neurological sequalae were noted in our cohort, despite rechallenging. Therefore in our study, methotrexate induced neurotoxicity is a self-limiting toxicity and methotrexate can be re-challenged safely without compromising theintensity of CNS-directed therapy.
Methotrexate (MTX) is one of the mainstay drugs used in acute lymphoblastic leukemia (ALL) management; however, it can cause damage to the central nervous system (CNS), typically to the subcortical white matter. Stroke-like syndrome is one particular form of MTX-related neurotoxicity that occurs within 21 days of methotrexate administration (intrathecal or high-dose intravenous treatment). The clinical picture comprehends fluctuating neurological symptoms evoking acute cerebral ischemia or hemorrhage (paresis or paralysis, speech disorders - aphasia and/or dysarthria, altered mental status, and occasionally seizures), with spontaneous resolution in the majority of cases, without other identifiable cause. The typical neuroimage includes areas of restricted diffusion on diffusion-weighted imaging and non-enhancing T2 hyper-intense lesions in the white matter, on brain MRI. We report a 12-year-old boy with low-risk B-ALL without CNS involvement, who presented to the emergency department with complaints of sudden paresis of the four limbs (more severe on the right side), aphasia, and confusion. He had received one dose of intrathecal MTX 11 days prior to this episode. An angio-MRI of the brain revealed bilateral restricted diffusion areas in the centrum semiovale, and symptoms fluctuated until complete neurological recovery without any medical intervention, which is very suggestive of MTX-related neurotoxicity. This case illustrates a rare complication of MTX administration that presented with typical clinical and radiological characteristics, in an adolescent with hematological malignancy who experienced swift and full neurological recovery.
