Computed tomography scans of the brain in acute leukemia and lymphoblastic lymphoma. Follow-up of children receiving prophylactic central nervous system irradiation

Twenty-seven long-term survivors diagnosed between 1971 and 1977 as having acute lymphoblastic leukemia (23 children), acute myeloblastic leukemia (1 child), and lymphoblastic lymphoma (3 children) have been studied using CT scans of the brain. None of the children had ever had symptoms or signs of CNS involvement. CT scanning was performed in 19 cases at the cessation of therapy; in the other eight cases, CT scanning was performed 24 to 49 months after the end of therapy. In all children, CNS prophylaxis included cranial irradiation with 24 Gy. Six children were also given spinaJ radiation, while in the remaining 21 cases intrathecal Methotrexate was given 5–6 times. CT scans of the brain showed slight abnormalities with increased ventricular size in only two cases. No differences in attenuation or intracranial calcifications were found. (CT = Computed Tomography, ALL = Acute Lymphoblastic Leukemia, AML = Acute Myeloblastic Leukemia, CNS = Central Nervous System). Acute leukemia, brain, children, CT scan, lymphoma.     

Computed tomography brain scans in long term survivors of childhood acute lymphoblastic leukemia

There have been varying frequencies cited for the occurrence of abnormal brain CT scans in Jeukemic patients and confiding evidence about the significance of these abnormalities and their relationship to sanctuary therapy. Our study of CT brain scans in 26 long survivors of acute lymphoblastic leukemia showed an overall prevalence of 35% abnormal scans. There was no statistically significant difference between the number of abnormal scans seen in patients given radiotherapy as part of their CNS prophylaxis and those receiving only intrathecal methotrexate. Because the children in each treatment group were evenly matched with respect to other treatment variables possibly relevant to the causation of abnormal brain scans, a strong case is made for more rigorous design of such studies, preferably in a prospective fashion, looking simultaneously at other parameters of brain structure and function.     

Cranial computed tomography findings in children with acute lymphoblastic leukemia at diagnosis

Forty children newly diagnosed with acute lymphoblastic leukemia (ALL) were examined by computed tomography (CT) of the central nervous system (CNS) on hospital admission before any medication was started. The results of the CT scans were defined as normal, borderline (slight or moderate dilatation of the ventricular system and/or basal cisterns and/or convolutional sulci), or pathologic (severe cerebral atrophy). The mean age of the patients was 5.8 years (range 1.7-15 years). Sixteen of the 40 patients (40%) had CT scan abnormalities with 14 patients having borderline scans and two patients pathologic scans. No child presented with neurologic symptoms or CNS leukemia. These data suggest that CT abnormalities of the brain are common in children with ALL at diagnosis and may represent clinically unsuspected lesions secondary to leukemia.     

Reversible Changes on Computed Tomography Scans of the Brain During Induction Therapy for Acute Lymphoblastic Leukemia in Children

Children with acute lymphoblastic leukemia (ALL) have been shown to develop changes on computed tomography (CT) scans of the brain. These changes are seen both during and after therapy. Some of the results have been contradictory.

Nine children with ALL were examined by CT of the brain during induction therapy. All children showed normal CT scans on the day of diagnosis. One month later all had dilatation of the ventricles and widened sulci. During the next 9 months the CT scans gradually were normalized. We conclude that such changes in CT scans of the brain are transitory and are caused by the high dose of prednisolone administered during induction therapy.     

Neuropsychological status of children with acute lymphoblastic leukemia treated for central nervous system relapse

Approximately 10% of children treated with contemporary therapy for acute lymphoblastic leukemia (ALL) will experience an isolated relapse in the central nervous system (CNS). From 5 to 25% of this group will become long-term survivors, but only after additional, more aggressive therapy. A review of the limited number of studies of children surviving treatment for CNS relapse disclosed a strikingly higher incidence of intellectual impairment than was found in similarly treated patients who remain in complete remission. Specific risk factors for this complication included the number of courses of cranial irradiation, a young age at treatment, increasing time since treatment, neuropathological changes apparent on abnormal computed tomography scans of the brain, and seizures. The methodological problems inherent in neurobehavioral research in childhood acute lymphoblastic leukemia are critically reviewed and suggestions for future studies are offered. Children with a CNS relapse should be serially evaluated for psychoeducational performance to facilitate early intervention in cases of learning difficulties.     

Computed tomographic findings of the brain in children with acute lymphocytic leukemia after central nervous system prophylaxis without cranial irradiation.

Nineteen children in primary remission of acute lymphocytic leukemia (ALL) were investigated by computed tomographic (CT) scans of the brain 2 to 64 (mean 19) months after the central nervous system (CNS) prophylaxis was finished. The CNS prophylaxis consisted of high dose Methotrexate (HDM) intravenously combined with 6--8 doses of Methotrexate intrathecally. Two children received only Methotrexate intrathecally as CNS prophylaxis. In addition three children with ALL who had CNS leukemia were investigated by CT scans of the brain. Only one abnormal CT scan was found among the nineteen asymptomatic children, and one of the three patients with CNS relapse had slightly dilatated subarachnoidal spaces. These results compared with other reports in literature in which the CNS prophylaxis has consisted of intrathecal Methotrexate and cranial irradiation, suggest that there are fewer abnormal CT findings of the brain in patients not receiving cranial irradiation as part of CNS prophylaxis.     

COMPUTED TOMOGRAPHIC FINDINGS OF THE BRAIN IN CHILDREN WITH ACUTE LYMPHOCYTIC LEUKEMIA AFTER CENTRAL NERVOUS SYSTEM PROPHYLAXIS WITHOUT CRANIAL IRRADIATION

Abstract. Nineteen children in primary remission of acute lymphocytic leukemia (ALL) were investigated by computed tomographic (CT) scans of the brain 2 to 64 (mean 19) months after the central nervous system (CNS) prophylaxis was finished. The CNS prophylaxis consisted of high dose Methotrexate (HDM) intravenously combined with 6–8 doses of Methotrexate intrathecally. Two children received only Methotrexate intrathecally as CNS prophylaxis. In addition three children with ALL who had CNS leukemia were investigated by CT scans of the brain. Only one abnormal CT scan was found among the nineteen asymptomatic children, and one of the three patients with CNS relapse had slightly dilatated subarachnoidal spaces. These results compared with other reports in literature in which the CNS prophylaxis has consisted of intrathecal Methotrexate and cranial irradiation, suggest that there are fewer abnormal CT findings of the brain in patients not receiving cranial irradiation as part of CNS prophylaxis.     

CRANIAL COMPUTED TOMOGRAPHY DURING TREATMENT OF CHILDHOOD LYMPHOCYTIC LEUKEMIA

ABSTRACT. Twenty-three children with acute lymphocytic leukemia (ALL) were examined by computed tomography (CT) of the head on two occasions more than 11 months apart. The first CT was performed at the time of diagnosis in 11 children, who were re-examined while still in their first complete remission. They had received prophylactic central nervous system (CNS) treatment consisting of intrathecal methotrexate supplemented by irradiation in 7 cases and intermediate dose methotrexate in 4 cases. Twelve children were receiving treatment for CNS relapse. This included therapeutic irradiation and intrathecal methotrexate. Abnormal CT developed in 7 children. Three CT scans demonstrated areas of decreased attenuation coefficient, one with intracerebral calcifications. In 5 patients, dilatation of the ventricles and cortical sulci had developed. AU CT abnormalities occurred in children in remission after CNS relapse. These results indicate that prophylactic treatment including cranial irradiation with 24 Gy and low cumulative doses of methotrexate is a safe procedure. Patients with CNS leukemia are at risk of developing CNS abnormalities, when they receive treatment with cranial irradiation and methotrexate. The risk is not correlated with age or sex of the child, the duration of the disease, the dose of irradiation or the cumulative dose of methotrexate.     

Cranial computed tomographic findings in children with newly diagnosed acute lymphoblastic leukemia: A prospective follow-up study during treatment

Cranial computed tomography (CT) was performed on 40 consecutive children with newly diagnosed acute lymphoblastic leukemia (ALL) on admission before any chemotherapy, 5 months after CNS therapy (n = 39) and after 2 to 3 years of therapy (n = 31). Changes related to leukemia were found in only 10% of the patients at the time of diagnosis (4/40). These initial changes, two intracranial hemorrhages, one dural thickening and one contrast enhancement, all disappeared during therapy. The findings which persisted unchanged in the next two CT scans were thought to be normal variations or caused by earlier disorders. CNS therapy consisted of intrathecally and intravenously administered methotrexate in 20 standard risk (SR) patients and cranial irradiation in addition to chemotherapy in 19 intermediate risk (IR) or high risk (HR) patients. Four SR patients developed changes during therapy. Three had enlarged cerebrospinal fluid (CSF) spaces and one developed a focal low density area suggesting disturbances in brain blood circulation and also experienced disturbances in level of consciousness. Of the 19 IR or HR patients, eight developed changes related to the therapy, including four with white matter hypodensity areas, of whom three also had enlarged CSF spaces, and four others who developed enlarged CSF spaces. The medians of the widths of the cortical sulci (P < .001), insular cisterns (P < .01), third ventricles (P < .01), and frontal horns (P < .05), and also of Evans' ratios (P < .05) increased significantly after CNS therapy as compared with the findings at diagnosis in the patients who had received cranial irradiation. Most of these changes persisted during the follow-up. We conclude that the clinical value of CT scanning during therapy for ALL is restricted to patients with neurological symptoms or those who have undergone CNS irradiation. © 1992 Wiley-Liss, Inc.     

儿童急性白血病合并中枢神经系统真菌感染5例并文献复习

目的通过5例儿童急性白血病合并中枢神经系统(CNS)真菌感染的临床总结及相关文献复习,提高对本病的认识。方法回顾性分析北京儿童医院收治的5例急性白血病合并CNS真菌感染患儿的临床特点及诊治经过并文献复习。结果(1)4例急性淋巴细胞白血病(ALL)患儿均接受强化疗,1例为急性非淋巴细胞白血病(AML-M2)半相合造血干细胞移植术后,发生CNS真菌感染前均有肺部真菌感染病史,其中2例合并肝、脾、肾真菌感染,1例合并下肢皮肤真菌感染(2)实验室检查3例有病原学依据,1例烟曲霉菌,2例念珠菌,2例无病原学依据。(3)影像学5例患儿均作头颅CTMRI,表现脓肿、梗塞、颅内出血。(4)治疗及预后1例患儿伊曲康唑+脂溶性两性霉素B治疗,2例患儿伏立康唑治疗,2例患儿伏立康唑和两性霉素B联合抗真菌治疗,抗真菌治疗均有效,4例存活,1例死于严重移植物抗宿主病(GVHD)。结论儿童急性白血病合并CNS真菌感染为侵袭性真菌感染的表现形式之一,多半有其他脏器感染,临床表现不典型,可有脑膜炎或脑脓肿症状和体征,诊断困难,CT、MRI影像学检查重要,伏立康唑、两性霉素B抗真菌治疗有效。     

Creatinine as a measure of lean body mass during treatment of acute lymphoblastic leukemia in childhood

Protein energy malnutrition is well-recognized in children with acute leukemia and may result in loss of lean body mass (LBM) with attendant morbidities. Much of the LBM consists of skeletal muscle, the mass of which is reflected in urinary creatinine excretion. As accurate 24 hours urine collections are challenging in children, we investigated the prospect that serum creatinine concentration provides a measure of LBM. Eleven children with acute lymphoblastic leukemia were assessed at 7 time points (6-mo intervals) from diagnosis to 1 year after the completion of therapy. LBM was measured as fat-free mass by dual energy x-ray absorptiometry (DXA scans) and correlated with serum creatinine concentration and 24 hours urine creatinine excretion. As expected, there was a strong correlation between 24 hours urinary creatinine excretion and LBM from DXA scans (r=0.79, P<0.001). Serum creatinine concentration also correlated with LBM (r=0.52, P<0.001). Serum creatinine concentration provides a surrogate measure of LBM in children with acute lymphoblastic leukemia. This will be especially useful in countries with limited resources in which more sophisticated measures, such as DXA scans, are seldom available.     

CENTRAL NERVOUS SYSTEM LYMPHOMA IN CHILDREN

This paper describes the rare MR and CT features of central nervous system (CNS) lymphoma in immunocompetent children and in survivors of childhood acute lymphoblastic leukemia (ALL) and discusses the causative role of cranial irradiation and/or leukoencephalopathy preceding central nervous system (CNS) lymphoma in survivors of childhood leukemia. The authors reviewed MR and CT scans of 3 children with biopsy-proved CNS lymphoma. One child had tumor infiltration within the optic nerve sheaths and optic chiasm by previously known non-Hodgkin lymphoma. In 2 patients, CNS lymphoma developed 8 and 10 years after initial ALL treatment. In both cases CNS lymphoma was preceded by cranial irradiation and leukoencephalopathy. A single lesion was present in 3 out of 4 patients. All lesions were isointense or hypointense on the T1-weighted images relative to gray matter and showed homogeneous enhancement. One lesion was centered in the central gray matter, one lesion was centered within a cerebral hemisphere, one lesion was in optic nerve, and there were 2 parasellar lesions. CNS lymphoma has a variable appearance in children. Knowledge of risk factors in children may help in the early recognition of disease, allowing for timely intervention. This may prompt early biopsy or a conservative management in the appropriate clinical setting.     

Central nervous system lymphoma in children

This paper describes the rare MR and CT features of central nervous system (CNS) lymphoma in immunocompetent children and in survivors of childhood acute lymphoblastic leukemia (ALL) and discusses the causative role of cranial irradiation and/or leukoencephalopathy preceding central nervous system (CNS) lymphoma in survivors of childhood leukemia. The authors reviewed MR and CT scans of 3 children with biopsy-proved CNS lymphoma. One child had tumor infiltration within the optic nerve sheaths and optic chiasm by previously known non-Hodgkin lymphoma. In 2 patients, CNS lymphoma developed 8 and 10 years after initial ALL treatment. In both cases CNS lymphoma was preceded by cranial irradiation and leukoencephalopathy. A single lesion was present in 3 out of 4 patients. All lesions were isointense or hypointense on the T1-weighted images relative to gray matter and showed homogeneous enhancement. One lesion was centered in the central gray matter, one lesion was centered within a cerebral hemisphere, one lesion was in optic nerve, and there were 2 parasellar lesions. CNS lymphoma has a variable appearance in children. Knowledge of risk factors in children may help in the early recognition of disease, allowing for timely intervention. This may prompt early biopsy or a conservative management in the appropriate clinical setting.     

The influence of traumatic lumbar puncture and timing of intrathecal therapy on outcome of pediatric acute lymphoblastic leukemia

The CNS is a frequent site of relapse of childhood acute lymphoblastic leukemia (ALL). Traumatic lumbar puncture (TLP) is thought to increase the risk of CNS relapse. The authors examined whether TLP at the time of diagnosis affected outcome and whether this effect was influenced by the timing of intrathecal therapy (IT) in 77 patients with newly diagnosed ALL. IT was instilled at the time of either the diagnostic LP (early) or a second LP 24-48 h later (delayed). Of the 19 patients who had a TLP at diagnosis and received late IT therapy, 6 had isolated CNS relapse and 2 had combined CNS and bone marrow (BM) relapse. Of the 9 patients who had TLP and received early IT therapy, 1 had a CNS relapse (p = .20). In an analysis stratified according to risk of relapse, the odds ratio (OR) for relapse was 0.8 among patients at low and standard risk who had delayed IT therapy after TLP (p = .99) vs. 0.17 for those who had early IT (p = .47). Importantly, among patients with high-risk ALL, the OR for relapse was 21.0 for delayed IT therapy (p = .09) and only 1.5 for early IT therapy after TLP (p = .99). The results indicate that TLP at diagnosis appears to increase the risk of CNS relapse markedly in patients with high-risk ALL, and the use of early IT therapy appears to reduce this risk. These findings need to be confirmed by prospective, randomized studies.     

Association of -24CT, 1249GA,and 3972CT ABCC2 Gene Polymorphisms with Methotrexate Serum Levels and Toxic Side Effects in Children with Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia patients after being treated with methotrexate, have differences in methotrexate serum levels and toxic side effects. One of the main determinants of these toxic side effects is the host pharmacogenetics. The aim of this study was to evaluate the association of -24CT, 1249GA, and 3972CT ABCC2 gene polymorphisms with serum levels, and toxic side effects of methotrexate in childhood acute lymphoblastic leukemia. Applying polymerase chain reaction and restriction fragment length polymorphism techniques, the prevalence of -24CT, 1249GA, and 3972CT ABCC2 gene polymorphisms was evaluated in 65 acute lymphoblastic leukemia patients. The relationship between polymorphisms and methotrexate serum levels and toxicities was studied. A reverse significant relationship was detected between 3972T allele carriers and hepatotoxicity (P = 0.01, OR = 0.25, 95% CI = 0.09–0.72). Also, 1249A allele carriers had increased rate of gastrointestinal toxicity (P = 0.05, OR = 3.47, 95% CI = 1.04–11.57). No significant relationship was detected between -24CT polymorphism and methotrexate toxic side effects. There was no significant relationship between these three polymorphisms and methotrexate serum levels. Genotyping for 3972CT and 1249GA ABCC2 gene variants maybe useful in acute lymphoblastic leukemia to optimize methotrexate therapy and reducing the associated toxicity.     

Immunization response varies with intensity of acute lymphoblastic leukemia therapy.

Twenty-four children receiving maintenance chemotherapy for acute lymphoblastic leukemia were given booster doses of tetanus-diphtheria combined toxoids. One month later, 19 of the 24 children were given Haemophilus influenzae B oligosaccharide-cross-reacting material conjugate vaccine. Following immunization, all patients had protective antibody titers against tetanus, 92% had protective antidiphtheria titers, and 84% had protective titers against H influenzae. Preimmunization titers, postimmunization titers, and response to immunization varied according to the intensity of therapy. There was no correlation with duration of therapy or quantitative hematologic values in the peripheral blood. These observations support the recommendation that children treated for acute lymphoblastic leukemia should be immunized against H influenzae B.     

Reproduction following treatment for childhood leukemia: a population-based prospective cohort study of fertility and offspring

Of all children diagnosed with leukemia in Denmark, Finland, Iceland, Norway, and Sweden, 981 had discontinued therapy before 1985 and had been followed up annually after cessation of therapy. Progeny was registered and fertility evaluated among survivors who passed age 18 years without a relapse (n = 299). By April 1989, 48 offspring were registered, one of whom had congenital anomalies. This was no more than expected from the incidence of birth defects in the general population. No childhood malignancies or genetic diseases have so far been diagnosed in the progeny. In the study group, none of the 19 female and 8 male survivors of myeloid leukemias had become parents, and only 4 fathers were reported among the 131 male survivors of acute lymphoblastic leukemia (ALL). However, 23 of the 149 females treated for ALL had delivered 41 children. Fertility was measured as cumulative rates of first birth by maternal age. In a Cox regression analysis, cases who had received prophylactic radiation of the central nervous system (CNS) had a lower first birth rate than those without radiation (rate ratio 0.39, 95% CI 0.15-1.00), indicating that doses of 18-24 Gy to the brain may possibly be a risk factor. By using the Norwegian birth cohort of 1966 as a control group, matching the median year of birth for the study subjects, the group of female ALL survivors as a whole was as likely as the general female population to have given birth up to the age of 23. The first generation of females successfully treated for childhood ALL seems to have a nearly normal reproductive pattern during young adulthood, without increased risk of congenital anomalies in the offspring. However, cranial radiation as CNS prophylaxis may possibly impair subsequent reproduction.     

Neurotoxicity due to central nervous system therapy for childhood leukemia

Therapy for occult or overt meningeal leukemia produces subclinical or clinical neurotoxicity in a variable proportion of children with acute lymphoblastic leukemia (ALL). The type, frequency, and permanence of these central nervous system (CNS) changes depend primarily on the therapy itself, although the contribution of additional factors, such as young age, may be substantial. Neurotoxicity in patients who have received 2,400 cGy cranial irradiation plus 5 concurrent doses of intrathecal methotrexate as CNS prophylaxis has been characterized more fully than the CNS changes accompanying other forms of therapy. Cross-sectional studies using cranial computed tomography scans to evaluate structural changes in the brain have shown ventricular dilatation in 15%, white matter hypodensity in 3.5%, and calcifications in 8%. The principal neuroendocrine effect is decreased growth velocity during therapy and adolescence, with significant decreases in final height in approximately one-third of children. Secondary cerebral gliomas with a poor prognosis are being reported with increasing regularity, but the true risk of this complication is still unknown. Use of parenteral methotrexate as the sole method of CNS prophylaxis is associated with transient focal white matter hypodensity. Neuroendocrine and neuropsychologic sequelae associated with this therapy are minimal; however, much of the available information is based on patients treated with regimens that had unacceptably high CNS relapse rates or whose length of follow-up was brief. With more aggressive, and hence more effective, prophylaxis with intrathecal methotrexate, spinal cord myelopathy may become a significant new area of neurotoxicity. Clinically significant CNS toxicity develops in the majority of patients who receive treatment for meningeal relapse. The leukemia itself is a prime contributing factor to this neurotoxicity. In patients who are subsequently cured of leukemia, acute neurotoxicity consists mainly of seizures; the most significant sequelae appearing after the cessation of therapy consists of significant drops in full scale IQ.     

Elevation of cerebrospinal fluid sialic acid concentration in children with central nervous system leukemia

We studied sialic acid in the cerebrospinal fluid (CSF) of 52 children with leukemia and 51 children with non-leukemic diseases. The CSF sialic acid concentration in the children with central nervous system (CNS) leukemia was significantly higher than that in the children with acute lymphoblastic leukemia without CNS involvement, acute non-lymphocytic leukemia without CNS involvement, non-hemopoietic diseases, non-suppurative meningitis, epilepsy, and other neurologic diseases. Serial determinations revealed a rapid decline in the CSF sialic acid concentrations in the patients with CNS leukemia who responded well to the therapy and who were free from relapse of CNS leukemia. The simultaneously determined CSF beta 2 microglobulin concentration did not show any significant changes. These results suggest that the CSF sialic acid may be a good indicator of CNS leukemia.     

Elevation of Cerebrospinal Fluid Sialic Acid Concentration in Children with Central Nervous System Leukemia

ABSTRACT. We studied sialic acid in the cerebrospinal fluid (CSF) of 52 children with leukemia and 51 children with non-leukemic diseases. The CSF sialic acid concentration in the children with central nervous system (CNS) leukemia was significantly higher than that in the children with acute lymphoblastic leukemia without CNS involvement, acute non-lymphocytic leukemia without CNS involvement, non-hemopoietic diseases, non-suppurative meningitis, epilepsy, and other neurologic diseases. Serial determinations revealed a rapid decline in the CSF sialic acid concentrations in the patients with CNS leukemia who responded well to the therapy and who were free from relapse of CNS leukemia. The simultaneously determined CSF β2 microglobulin concentration did not show any significant changes. These results suggest that the CSF sialic acid may be a good indicator of CNS leukemia.