Acute fever and delayed leukoencephalopathy following low dose intraventricular methotrexate.

Nine out of 14 patients treated with intraventricular methotrexate (MTX) for meningeal carcinomatosis from breast carcinoma and surviving more than 4 months developed disseminated necrotising leukoencephalopathy (DNL). All four patients who had received both intraventricular MTX and whole brain radiotherapy developed DNL. Five of the six patients who experienced an acute febrile reaction with mild encephalopathic signs following intraventricular administration of MTX developed DNL after a mean time of 5 months and a low mean dose of 44 mg MTX. DNL was also noted in two patients without a previous febrile reaction or whole brain radiotherapy, following prolonged intraventricular MTX therapy after a mean time of 19.5 months and a mean dose of 147 mg MTX. These findings confirm the hazards of (1) high cumulative doses of intrathecal MTX and (2) combined intrathecal chemotherapy and whole brain radiotherapy. This study also suggests a possible relationship between an early and transient febrile reaction during intraventricular administration of MTX and the development of DNL.     

Fulminant chemical ventriculomeningitis following intrathecal liposomal cytarabine administration

Intrathecal liposomal cytarabine (ITLC) has shown prolonged time to neurological deterioration in some patients with leptomeningeal spread of breast cancer. We describe a patient with fulminant chemical ventriculomeningitis leading to cerebral edema and death following ITLC administration. A 56-year-old Caucasian female developed progressive headache, depressed level of consciousness and adventitious movements immediately following ITLC. Neurological examination was normal prior to injection. This progressed to loss of all brainstem function and a head CT scan demonstrated diffuse cerebral edema. Due to the absence of neurological function on examination, the family opted to withdraw care. To our knowledge we report the first patient with fulminant chemical ventriculomeningitis leading to cerebral edema and death following ITLC administration. Adjunctive glucocorticoids are recommended. Treatment options are limited and complicated by the liposomal formulation of intrathecal cytarabine.     

Neurologic complications of chemotherapy.

Neurotoxicity is a common and potential dose-limiting complication of cancer chemotherapy. For most agents, high-dose therapy, combination chemotherapy, concomitant cranial radiotherapy, and intracarotid or intrathecal injection are more likely to produce neurologic complications than standard oral or intravenous therapy. Any portion of the nervous system can be damaged. Encephalopathies (either focal or diffuse) are produced by BCNU, cisplatin, cytarabine, 5-fluorouracil, ifosfamide, L-aspariginase, methotrexate, procarbazine, corticosteroids, and some biological response modifiers (interferon, interleukin-2). Cerebellar syndromes may follow the administration of cytarabine, 5-fluorouracil, and procarbazine. Myelopathy may complicate intrathecal methotrexate, cytarabine, thiotepa, and accidental intrathecal vincristine or doxorubicin injection. Peripheral neuropathy occurs from cisplatin, vincristine, and, sometimes, cytarabine or procarbazine. Myopathy is a common complication of corticosteroids. Strokelike syndromes may occur with L-aspariginase, high-dose methotrexate, and intracarotid BCNU or cisplatin. Differentiating the neurologic complications of chemotherapy from other neurologic complications of cancer is often difficult. As cancer patients are treated more aggressively, receive more chemotherapy, and live longer, and as new chemotherapeutic agents are developed and existing agents are used more intensively or in novel ways, neurologic complications of cancer chemotherapy will become more common, serious, and complex. The recognition and treatment of chemotherapy-induced neurotoxicity will become a frequent and important clinical problem for most neurologists.     

Intrathecal methotrexate affects cognitive function in children with medulloblastoma

BACKGROUND: Cognitive impairment occurs after malignant brain tumor treatment in children, following brain radiotherapy and systemic and intrathecal chemotherapy. OBJECTIVES: 1) To compare two groups of children who underwent surgery for cerebellar medulloblastoma with their cousins and siblings, assessing intelligence, executive function, attention, visual perception, and short-term memory. Both groups were treated with the same combined radiotherapy-chemotherapy, but differed in that only one group received intrathecal methotrexate (MTX+). 2) To relate these measures to MRI findings (leukomalacia). RESULTS: The two groups performed worse than their control subjects in all tests. The MTX+ group younger than 10 years performed significantly worse in all tests, particularly executive ones. The group older than 10 years performed significantly worse only in short-term memory. Younger patients without MTX performed significantly worse than controls only in some neuropsychological measures; there were no differences between older patients and control subjects. Only in the MTX+ group was there a direct correlation between extent of leukomalacia and performance in some tests. CONCLUSIONS: The administration of intrathecal methotrexate to children with medulloblastoma worsens the cognitive deficits induced by chemotherapy and radiotherapy. The use of intrathecal methotrexate in the treatment of medulloblastoma and other malignancies should be reassessed.     

Myelopathy mimicking subacute combined degeneration in a Down syndrome patient with methotrexate treatment for B lymphoblastic leukemia: Report of an autopsy case

We report clinicopathological features of a 23‐year‐old woman with Down syndrome (DS) presenting with subacute myelopathy treated with chemotherapy, including intravenous and intrathecal administration of methotrexate (MTX), and with allogenic bone‐marrow transplantation for B lymphoblastic leukemia. Autopsy revealed severe demyelinating vacuolar myelopathy in the posterior and lateral columns of the spinal cord, associated with macrophage infiltration, marked axonal loss and some swollen axons. Pathological changes of posterior and lateral columns were observed from the medulla oblongata to lumbar cord. Proximal anterior and posterior roots were preserved. Cerebral white matter was relatively well preserved. There were no vascular lesions or meningeal dissemination of leukemia. Longitudinal extension of cord lesions was extensive, unlike typical cases of subacute combined degeneration (SACD), but distribution of lesions and histological findings were similar to that of SACD. DS patients show heightened sensitivity to MTX because of their genetic background. Risk factors for toxic myelopathy of DS are discussed, including delayed clearance of MTX despite normal renal function, alterations in MTX polyglutamation and enhanced folic acid depletion due to gene dosage effects of chromosome 21. Alteration of folate metabolism and/or vitamin B₁₂ levels through intravenous or intrathecal administration of MTX might exist, although vitamin B₁₂ and other essential nutrients were managed using intravenous hyperalimentation. To the best of our knowledge, this is the first report of an autopsy case that shows myelopathy mimicking SACD in a DS patient accompanied by B lymphoblastic leukemia. The case suggests a pathophysiological mechanism of MTX‐related myelopathy in DS patients with B lymphoblastic leukemia mimicking SACD.     

Recent Advancements of Treatment for Leptomeningeal Carcinomatosis

Treatment of Leptomeningeal carcinomatosis (LMC) from solid cancers has not advanced noticeably since the introduction of intra-cerebrospinal fluid (CSF) chemotherapy in the 1970''s. The marginal survival benefit and difficulty of intrathecal chemotherapy injection has hindered its wide spread use. Even after the introduction of intraventricular chemotherapy with Ommaya reservoir, frequent development of CSF flow disturbance, manifested as increased intracranial pressure (ICP), made injected drug to be distributed unevenly and thus, the therapy became ineffective. Systemic chemotherapy for LMC has been limited as effective CSF concentration can hardly be achieved except high dose methotrexate (MTX) intravenous administration. However, the introduction of small molecular weight target inhibitors for primary cancer treatment has changed the old concept of ''blood-brain barrier'' as the ultimate barrier to systemically administered drugs. Conventional oral administration achieves an effective concentration at the nanomolar level. Furthermore, many studies report that a combined treatment of target inhibitor and intra-CSF chemotherapy significantly prolongs patient survival. Ventriculolumbar perfusion (VLP) chemotherapy has sought to increase drug delivery to the subarachnoid CSF space even in patients with disturbed CSF flow. Recently authors performed phase 1 and 2 clinical trial of VLP chemotherapy with MTX, and 3/4th of patients with increased ICP got controlled ICP and the survival was prolonged. Further trials are required with newly available drugs for CSF chemotherapy. Additionally, new LMC biologic/pharmacodynamic markers for early diagnosis and monitoring of the treatment response are to be identified with the help of advanced molecular biology techniques.     

Intrathecal chemotherapy for refractory disseminated medulloblastoma

Objective To analyze the effect of intrathecal (IT) chemotherapy for disseminated medulloblastoma. Materials and methods Twenty-one patients received IT chemotherapy using the chemotherapeutic agents of methotrexate (MTX) and nitrosoureas (ACNU, MCNU) including nine patients for residual leptomeningeal lesions after initial surgery and radiation, and 12 for a recurrence with leptomeningeal dissemination. Of these 21 patients, 12 received a lumbar and/or ventricular bolus injection of the chemotherapeutic agents, one received the ventriculolumbar perfusion of the agents, and eight received both the perfusion and bolus injection. The doses ranged from 6–7 mg/m² of ACNU for perfusion and 3–3.5 mg/m² of ACNU, MCNU, or MTX for the bolus injection, and the cycles were administered from 3 to 12 times for perfusion and from 5 to 54 times for the bolus injection. The effects of chemotherapy were assessed by both radiological and cytological examinations, and the clinical symptoms were also assessed. Radiological and/or cytological responses were observed in 10 of 21 patients (47.6%), including seven cases demonstrating a complete remission. The 5-year overall survival rate and 5-year survival rate after dissemination were 61.5 and 46.4%, respectively. Five patients who received a lumbar bolus injection of nitrosoureas experienced paraplegia and double incontinence. One patient who received a ventricular injection of nitrosoureas experienced truncal ataxia. Conclusion IT chemotherapy was found to be effective in some cases with refractory disseminated medulloblastoma and it seems to be an appropriate treatment choice for leptomeningeal recurrence. However, the frequent bolus injections of nitrosoureas should be avoided to prevent the side effects.     

Methotrexate myelopathy with extensive transverse necrosis: Report of an autopsy case

The patient was a 70‐year‐old woman with lymphoplasmacytic lymphoma which showed a predominantly diffuse involvement of the bone marrow and kidney. Because atypical lymphocytes appeared in the cerebrospinal fluid, the intrathecal administration of methotrexate (MTX) and cytosine arabinoside (Ara‐C) was repeated several times. The patient developed flaccid paraplegia 8 months after the beginning of intrathecal administration, and died 4 months later. Autopsy demonstrated extensive transverse necrosis involving the lower thoracic cord and marked vacuolar degeneration of the white matter of the cervical, upper thoracic and lumbo‐sacral cord. Focal vacuolar degeneration of the white matter was also noted in the left parietal lobe. Although vacuolar degeneration of the white matter is a common feature in MTX myelopathy, extensive transverse necrosis is rare. In the present case, an overlapping of two mechanisms, that is, injury of vascular endothelial cells and the direct toxic effect of MTX and Ara‐C on the white matter, probably played a crucial role in the pathogenesis of severe myelopathy. Because severe myelopathy occurs infrequently, considering the large number of patients receiving the intrathecal administration of MTX, it is possible that a constitutional predisposition or abnormal sensitivity to MTX was involved in the pathogenesis in the present patient.     

Neurotoxicity due to methotrexate in paediatric patients. Description of the clinical symptoms and neuroimaging findings

INTRODUCTION. High-dose methotrexate (MTX) has showed to increase the surveillance in children with acute lymphoblastic leukemia and other neoplasms. However, MTX may induce significant neurotoxicity. AIM. To evaluate, in our population of patients who have been treated with MTX, the incidence of neurotoxicity and to describe its main clinical and radiological characteristics. PATIENTS AND METHODS. We retrospectively review the patients who received treatment with systemic high-dose MTX and/or intrathecal MTX between 1994 and 2010. The children who presented clinical o radiological signs of neurotoxicity were reviewed. RESULTS. We identified 284 patients who received high-dose intravenous and/or intrathecal MTX. 9 patients presented neurotoxicity. The median age at diagnosis was 6 years; 6 patients were male. The diagnosis included: 6 acute lymphoblastic leukemia, 2 medulloblastoma and 1 lymphoma. 66% patients presented focal neurological dysfunction, 3 had non-specific symptoms. In 5 patients the symptomatology started the first 14 days after the MTX administration. 8 patients had complete clinical resolution, but only one presented neurological long term effects. All the patients except one showed signs of acute leukoencephalopathy in the brain MR study. These alterations resolved one year later in 3 patients; in the other patients the MR alterations persisted. The neurotoxicity management was corticosteroid, folinic acid, aminophylline and dextromethorphan. CONCLUSION. The MTX neurotoxicity it can present as acute or chronic. It has a wide clinical spectrum, ranging from sub-clinical manifestations with complete recovery to a chronic and progressive encephalopathy.     

Severe complications after intrathecal methotrexate (MTX) for treatment of primary central nervous system lymphoma (PCNSL)

Primary central nervous system lymphoma (PCNSL) is a rare and highly malignant tumor with increasing incidence. Survival has improved with the use of nonsurgical treatment modalities, of which methotrexate (MTX)-based intrathecal chemotherapy has been an important option. Here, we describe devastating complications in three patients with diffuse large B-cell lymphomas. After intrathecal MTX therapy two patients died secondary to fulminant brain edema. A third patient developed severe dementia, gait disturbance and urinary incontinence due to leukencephalopathy. Since bulky disease was present in all three patients, CSF flow may have been impaired. This might have exposed adjacent tissue to prolonged toxic drug concentrations. Regarding the severe complications seen in these patients, it is useful to consider high-dose intravenous MTX treatment only in periventricular PCNSL.     

Diagnosis and therapy of meningosis neoplastica]

Metastatic leptomeningeal disease occurs in 5-30% of patients with breast or lung cancer, malignant melanoma, non-Hodgkin's lymphoma, leukemia and primary malignant brain tumors. Intrathecal chemotherapy with methotrexate, cytarabine, or thiotepa combined with irradiation of the site of major involvement increases overall median survival from 1-2 months to 2-7 months. Clinical outcome is limited by progression of systemic or CNS disease and by the neurotoxic side effects of therapy, i.e. leukoencephalopathy. New immunotherapeutic strategies of intrathecal treatment may be effective and less toxic, but are not yet sufficiently defined and available. This review covers the current diagnostic and therapeutic features of metastatic leptomeningeal disease. Pragmatic therapeutic recommendations, based on available clinical knowledge are given with special consideration of the side effects of therapy.     

Ventral polyradiculopathy with pediatric acute lymphocytic leukemia.

A 3-year-old girl with acute lymphocytic leukemia (ALL) in remission developed lower extremity paraparesis and areflexia 15 days after receiving intrathecal methotrexate, cytarabine, and hydrocortisone. Cerebrospinal fluid protein was 107 mg/dl. Compound muscle action potential amplitudes were reduced, F waves were absent, and sensory conduction studies were normal. Needle electromyography (EMG) revealed reduced motor unit potential recruitment. Magnetic resonance imaging (MRI) showed lumbosacral ventral root enhancement. She was treated with intravenous immunoglobulin and slowly recovered. Nerve conduction and EMG abnormalities correlated with MRI root enhancement, facilitated early diagnosis, and distinguished this from a myelopathy or distal polyneuropathy. These findings could represent selective ventral nerve root vulnerability to intrathecal chemotherapy. A selective autoimmune process cannot be excluded.     

鞘内注射甲氨蝶呤和氟美松治疗重症中枢神经狼疮疗效分析

目的探讨甲氨蝶呤联合氟美松鞘内注射治疗系统性红斑狼疮(SLE)中枢神经系统损害的效果。方法对28例鞘内注射的SLE中枢神经系统损害患者治疗前后的临床表现、脑脊液、头颅CT或磁共振成像(MRI)进行对比分析,并与57例未行鞘内注射者的情况进行对照。结果28例患者中2例死亡,其他患者病情均明显改善或完全缓解;脑脊液压力明显下降,蛋白水平降低,糖升高,但差异无统计学意义;6例抗核抗体(ANA)阳性者全部转阴。结论甲氨蝶呤联合氟美松鞘内注射治疗SLE中枢神经系统损害有明显效果,尤其是有定位表现者,能提高抢救成功率,副作用轻且少,值得临床推荐使用。     

Combined systemic and intraventricular chemotherapy in primary CNS lymphoma: a pilot study

The objective was to evaluate response rate, response duration, and toxicity after systemic and intraventricular chemotherapy in primary CNS lymphoma (PCNSL). From September 1995 to September 1998, 20 consecutive patients with PCNSL (median age 64, range 27 to 71 years) were enrolled in a pilot study evaluating chemotherapy without radiotherapy. A high dose methotrexate (MTX) (cycles 1, 2, 4, 5) and cytarabine (ara-C) (cycles 3, 6) based systemic therapy (including dexamethasone, vinca alkaloids, ifosfamide, and cyclophosphamide) was combined with intraventricular MTX, prednisolone, and ara-C. Complete response was achieved in 11 and partial remission in two patients; in one response could not be determined. Four patients showed progressive disease and two (70, 71 years) died from treatment related complications. Observation time was 2 to 59 months (median 31.5 months). Kaplan-Meier estimate for median time to treatment failure (TTF) was 20.5 months, and for median survival 54 months. Systemic toxicity was mainly hematological. Ommaya reservoir infection occurred in four patients and acute transient MTX induced encephalopathy in two (subacute in another). Cognitive dysfunction possibly due to treatment was seen in only one patient after relapse and after a total of 12 cycles (six at relapse). In conclusion, primary chemotherapy based on high dose MTX and ara-C is highly efficient in PCNSL. Toxicity is manageable in patients younger than 70 years.     

Methotrexate-induced myelopathy mimicking subacute combined degeneration of the spinal cord

Methotrexate (MTX), a folate antagonist, is widely used to treat hematological malignancies. Although it is known to cause myelopathy, little is known about the pathophysiology and natural history of this myelopathy. We describe a 42-year-old woman with acute lymphoblastic leukemia who was treated with chemotherapy consisting of intrathecal MTX who developed a progressive myelopathy. The myelopathy mimicked, radiologically, subacute combined degeneration (SACD) of the spinal cord. This myelopathy mimicking SACD could be explained by the folate antagonism of MTX. The progressive clinical signs and serial MRI in this patient further our understanding of the natural progression of this myelopathy.     

Posterior leukoencephalopathy following intrathecal chemotherapy with MRA-documented vasospasm

Posterior leukoencephalopathy syndromes have been reported with hypertension, and immunosuppressive and chemotherapy agents. Cerebral vasospasm on MR angiography (MRA) has been noted in cases due to eclampsia. The authors report a case of Balint syndrome with irreversible posterior leukoencephalopathy on MRI following intrathecal methotrexate and cytarabine. Hypertension was not present. Diffuse, reversible arterial irregularities consistent with vasospasm were present on MRA during the acute illness.     

脑胶质瘤化疗敏感性实验研究

目的探讨脑胶质瘤细胞体外对化疗药物的敏感性，为临床有效治疗胶质瘤提供实验依据。方法采用四甲基偶氮唑盐微量酶反应比色法（MTT法）检测50例原代培养胶质瘤细胞在体外对替尼泊甙（VM-26）、卡氮芥（BCNU）、顺铂（CDDP）、长春新碱（VCR）、甲氨蝶呤（MTX）5种化疗药物单一或联合化疗的敏感性。结果42例获得药敏结果，成功率达84％。42例胶质瘤细胞对单一化疗药物的敏感性从高到低依次为VM-26〉BCNU〉CDDP〉VCR〉MTX。两种联合化疗方案（BCNU＋VM-26＋CDDP）和（BCNU＋VCR＋MTX）对胶质瘤细胞的敏感性明显优于单一用药（P〈0．01），且对绝大多数胶质瘤细胞增殖抑制率较高。结论两种联合化疗方案（BCNU＋VM-26＋CDDP）和（BCNU＋VCR＋MTX）可能对胶质瘤的化疗效果更好。     

Leptomeningeal carcinomatosis from breast cancer treated with intrathecal topotecan with concomitant intravenous eribulin

We present a patient with leptomeningeal carcinomatosis from breast cancer treated with intrathecal topotecan and intravenous eribulin. The regimen was well tolerated and provided clinical stability in a patient with progression on a prior intrathecal chemotherapy regimen.     

Primary B-cell lymphoma of the cauda equina, successfully treated with high-dose methotrexate plus high-dose cytarabine: a case report with MRI findings

Primary malignant lymphoma of the cauda equina is an extremely rare disease. Previously, there have been only 12 reported cases of malignant lymphoma of the cauda equina, and most cases relapsed early in the clinical course. So, the optimal treatment strategy for this condition has not been established yet and the prognosis is thought to be poor. We experienced a case of B-cell malignant lymphoma of the cauda equina, with rapid progression of the muscle weakness of the bilateral lower extremities, successfully treated with high-dose methotrexate plus high-dose cytarabine (Ara-C) chemotherapy, followed by radiotherapy and in complete remission without any recurrence signs, 1.5 years after the initial diagnosis. Intrathecal chemotherapy with MTX, Ara-C, and predonisolone was simultaneously performed. We should carefully continue to monitor the clinical course of our case, with the examinations of magnetic resonance imaging and cerebrospinal fluid in order not to overlook any subtle neurological changes or other clinical symptoms.     

Emergency treatment of life-threatening intrathecal methotrexate overdose

A male 34-year-old patient with aggressive diffuse malignant lymphoma was hospitalized for treatment. Because of high likelihood of CNS involvement, intrathecal methotrexate (MTX) 15 mg was administered with hydrocortisone 100mg. Shortly after the intrathecal injection the patient became agitated, and complained of severe low back pain and 2h later he became confused and developed generalized seizures. At this stage, it was realized that the dose contained 1200 mg of MTX (80-fold overdose). The patient developed ARDS and was comatose; he was intubated and transferred to ICU. The patient was immediately treated with intravenous leucovorin 1200 mg, and 15 mg every 6h, thereafter, for 72 h. In addition, CSF exchange with warm normal saline was initiated via intrathecal catheter, and a total of 200 ml of CSF were replaced during 48 h. Finally, at the end of the exchange 2 mg of leucovorin with 2 mg of dexamethasone were administered intrathecally. MTX levels in CSF 7h post-injection were 770 microM, and increased to 1250 microM 2h later. Thereafter, the levels in CSF declined, and 48 h post-injection were 47 microM. The plasma levels of MTX 7h post-injection were 10 microM, and declined to 0.7 microM at 68 h. The patient regained consciousness and underwent successful weaning from ventilator after tracheostomy. The highest reported intrathecal dose after which the patient survived was 625 mg. Due to the rarity of reported cases, there are no clear guidelines for treatment of massive intrathecal overdose. There is a controversy regarding the toxicity of intrathecal injection of leucovorin. We propose CSF exchange and intravenous leucovorin as the mainstay of treatment.