Leukemia is considered one of the most common childhood cancers. Long ago, the central nervous system complications of leukemia were rarely seen because the disease was rapid and fatal. Latterly, advances in imaging techniques and treatment methods have prolonged survival, but unfortunately, the frequency of CNS complications has increased. We divide the CNS complications of leukemia into those that result directly or indirectly from the underlying leukemic process and those related to treatment side effects [5, 7].
We prospectively evaluated the cranial MRI of 50 patients proved with leukemia ranging in age from 2 to 18 years and having CNS manifestations. Male represented 60% in our study, while females represented 40%.
ALL represented 86% of our cases, while AML represented 6%. Mixed phenotype leukemia and CML each represented 2%, while Burkitt’s leukemia represented 4%. This coordinated with previous studies of Verma et al. [2] and Terwilliger et al. [7] which stated that ALL is the most common type of leukemia.
In the current study, vascular disorders were the most common complication (58%), of which (34%) had sinovenous thrombosis, 20% had PRES, and 4% had a parenchymal hemorrhage.
Cerebral venous sinus thrombosis was considered the most common complication seen commonly in the maintenance phase 53% followed by the induction phase 41% and a few percentages 5% in the consolidation phase. The study performed by Malhotra et al. [8] and Porto et al. [9] said that cerebro-venous thrombosis was most common in the induction phase. Both studies have reported that venous sinuous thrombosis commonly happened post-exposure to L-asparaginase therapy in induction and maintenance phases. Treatment with L-asparaginase leads to the depletion of plasma proteins involved in both coagulation and fibrinolysis and has been linked to cerebrovascular complications including cortical infarcts, dural sinus thrombosis, intracerebral hemorrhage, and hemorrhagic infarcts. Cerebrovascular thrombosis or hemorrhage can also occur during anti-leukemic treatment as a result of leukocytosis, thrombocytopenia, sepsis, and coagulopathy [9]. This explains the sinovenous thrombosis in one of our patients in the consolidation phase apparently not related to asparaginase therapy.
For the diagnosis of venous thrombosis, the combination of conventional MR imaging with MRV could detect venous sinus thrombosis in all cases in our study. This agrees with multiple studies [10, 11] which stated that the combination of MR and MRV is now the method of choice because of its capability to reveal the absence of flow in the cerebral veins even with the absence of typical findings of brain infarcts. MRV can demonstrate the thrombus in the acute phase by the absence of flow which can be mistaken in conventional images for flowing blood.
PRES is a clinico-neuro-radiologic disease with distinct MR imaging findings, accompanied by clinical manifestations ranging from headache, altered mental status, seizures, and vision loss, to the loss of consciousness. In the current study, most cases diagnosed with PRES (70%) were detected early in the induction phase, while 10% in the consolidation phase, 10% in the maintenance phase, and 10% in the re-induction phase post-relapse. This agreed with Bianca et al. [12] and Raman [13] which have reported that cases with PRES tend to occur early in the induction phase. In the present study, MRI examinations showed typical features of PRES with the most frequently affected areas of the brain being the posterior regions, the occipital and posterior parietal regions (80%), followed by the frontal regions (60%), and the least commonly affected regions such as the cerebellum, thalami, basal ganglia, and pons which represented 10% per each. This matched with the study performed by Appachu et al. [14] and in accordance with the findings of the previous studies by Raman [13], Kastrup et al. [15], and McKinney [16].
Although hypertension is a risk factor for PRES, the blood pressure can be normal, particularly in the settings of chemotherapy and immunosuppressive therapy [13]. This is strongly supported by the study results, as most of the studied cases were normotensive apart from only two cases which had low blood pressure.
In the present study, we had two cases with hemorrhage: one had a frontal hematoma, and the other had parenchymal microbleeds. The MRI accurately detected parenchymal hematoma and microbleeds in the two cases. T2* images show high sensitivity in the detection of parenchymal microbleeds. This agreed with the study performed by Charidimou [17] that said the introduction of blood-sensitive MRI sequences, including T2*-GRE and susceptibility-weighted imaging (SWI), has enabled the accurate detection of cerebral microbleeds (CMBsO) (defined radiologically as small, rounded, homogeneous, hypointense lesions not seen with conventional spin-echo sequences). Also, the study by Beavers et al. [18] stated that GRE images were the most sensitive for the detection of retinal hemorrhages.
Another complication was cerebral infection. It represented 4% and was detected in two cases of the present study. Both cases had cerebral aspergillosis: one presented with multiple intra-axial masses, and the other had a solitary lesion at the midbrain. Both cases had AML in the early induction phase. The diagnosis of aspergillosis was confirmed by biopsy and detecting galactomannan antigens both in CSF and serum. One of the two patients with multiple masses unfortunately died, and the other patient improved with antifungal treatment. A study performed by Pandian et al. [19] stated that one of the major challenges in AML induction chemotherapy is the risk of death named induction mortality. One of the reasons which place AML patients at risk of acquiring various infections even before initiating induction chemotherapy could be the variable delay in seeking treatment. It is a well-known fact that the incidence and severity of infection depend on the duration of neutropenia. When the neutropenia is prolonged for more than 5 weeks, the chance of infection can be as high as 100%. The signal criteria show characteristic low signal foci with blooming artifacts in the wall and in the core of the lesions at gradient images corresponded to other prior studies by Marzolf et al. [20], Finelli et al. [21], and Luthra [22] which have assumed that this signal could be the result of either ferromagnetic fungal deposits (iron, manganese, magnesium, zinc) or the presence of methemoglobin (in the capsule wall and/or the macrophages) or the presence of free radicals produced by the macrophages.
Previous clinical studies by Marzolf et al. [20] and Gartner et al. [23] had suggested that doctors should exclude the presence of coexisting pulmonary or sinus infections. In the current study, CT examinations of the chest and sinuses were performed in both cases to exclude pulmonary and sinus aspergillosis, and they were positive.
Among the studied patients, 11 cases (22%) had CNS infiltration with leukemia whether cerebral, retinal, leptomeningeal, or craniofacial bone leukemic infiltration. In the present study, CNS infiltration was common in cases with ALL (63%), followed by Burkitt’s leukemia (18%), and then CML and AML (each represented 9%). This correlated with multiple studies by Charles et al. [24] and Del Principe et al. [25] which stated that CNS involvement in patients with AML is considerably less common than CNS involvement by acute lymphoblastic leukemia (ALL) in both adults and children.
In the present study, meningeal infiltration was detected in three cases. The first case showed enhanced dural thickening and subdural collection which were reported as inflammatory versus infiltration. CSF cytology revealed blast cells in CSF. The second showed multiple meningeal-based enhanced small masses at the brain and spine which were reported as infiltration. The last one showed diffuse ependymal enhancement and intra-ventricular masses. These cases were proved by CSF analysis and showed regression in the follow-up studies post-treatment with chemotherapy.
Cerebral parenchymal involvement was detected in two cases and appeared as multiple enhancing foci and ill-defined areas seen at the thalami, brain stem, and cerebellum which were reported as inflammatory versus infiltration. Further CSF analysis proved leukemic infiltration.
Among the cases of leukemic infiltration, there was one case with Burkitt’s leukemia that had a left orbital mass, proved by biopsy as leukemic infiltration. The MRI findings showed imaging characteristics that were compatible with those described by other studies [26,27,28,29].
In the present study, MRI had high sensitivity in the detection of retinal involvement in all three cases presented by focal retinal enhancement and thickening with enhanced nodules and diffusion restriction in DWI. This was proved by ophthalmic examination which showed subretinal fluid collection suggestive of infiltration. The follow-up studies showed marked improvement post-induction of chemotherapy. These findings corresponded to a study performed by Green et al. [30] and Pflugrath [31].
In the current study, MRI had detected bone marrow infiltration of the skull and maxillofacial bones in two cases by alteration of the marrow signal, cortical expansion, erosions, and associated soft tissue masses that showed post-contrast enhancement and diffusion restriction in DWI. This agreed with a study performed by Eisa [32] and Cao et al. [33] which said that MRI with DWI is a useful and non-invasive tool for detecting skull bone infiltration in ALL children before treatment and also the normalization of marrow signal at complete remission after therapy.
Toxicity related to high-dose methotrexate was detected in five patients presented by bilateral basal ganglia, periventricular regions, and centrum semi-oval areas with diffusion restriction and low ADC value. Subtle or no abnormal FLAIR signal was noted. These findings were similar to those described by Cruz-Carreras et al. [34] and Tando [35], as well as a study by Michael et al. [36] which concluded that DWI has the potential role for early detection of methotrexate white matter injury.
Periventricular leukoencephalopathy was detected in one case at the maintenance phase, presented by a periventricular deep white matter sheet of high FLAIR signal which was constant in follow-up studies and one case with atrophic brain changes post-end of therapy manifested by decreased cerebral volume and widened extra-axial CSF spaces. Both cases had no history of cranial irradiation. In a study performed by Porto et al. [9] said that atrophy of the brain was believed to be a late finding after irradiation related to a diffuse white matter injury, but other studies have suggested that the atrophic changes may be related to chemotherapy, with cranial irradiation playing a lesser role.
Mineralizing angiopathy was present in one case, which appeared as multiple calcific foci at the gray-white mater interface; this case had history of cranial radiation before the development of these calcifications. Calcifications were seen easily in non-contrast CT, while in MRI showed a faint bright signal at T1WI and a low signal at T2WI. This agreed with a study performed by Rossi [37] which stated that the best diagnostic radiologic tool for mineralizing microangiopathy is CT, which shows calcium deposition mainly localized in the basal ganglia and subcortical white matter.
