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Y Iqbal, JK Mah, V Palkar, R Al-Sudairy, MF Abdullah, A Al-Omari, Leukoencephalopathy and Cortical Laminar. Necrosis Ass

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Case Report

Leukoencephalopathy and Cortical Laminar Necrosis Associated with Intrathecal Methotrexate and Cranial Irradiation Yasir Iqbal, MD; Jean K. Mah, MD; Vijay Palkar, MD; Reem Al-Sudairy, MD; Mohammad F. Abdullah, MD; Ali Al-Omari, MD From the Department of Pediatric Oncology, Neurology and Radiology, King Fahad National Guard Hospital, Riyadh, Saudi Arabia Correspondence to: Dr. Y. Iqbal, P.O. Box 22490 Riyadh 11426 Saudi Arabia

Accepted for publication: December 2002

Y Iqbal, JK Mah, V Palkar, R Al-Sudairy, MF Abdullah, A Al-Omari, Leukoencephalopathy and Cortical Laminar Necrosis Associated with Intrathecal Methotrexate and Cranial Irradiation. 2003; 23(3-4): 167-170 With the advent of chemotherapy, mortality rates in children with acute lymphoblastic leukemia (ALL) have decreased. Though prophylactic treatment of the central nervous system (CNS) to prevent leukemic infiltration has dramatically reduced the incidence of CNS relapse and improved the survival in pediatric acute lymphoblastic leukemia, it is associated with serious sequelae. Various reports of neurotoxicity have been described, ranging from decreased intelligence quotient scores, impaired memory and attention span to severe leukoencephalopathy. 1We describe a unique case of neurotoxicity associated with prophylactic cranial irradiation and intrathecal MTX. Case report A four-year old boy was diagnosed as having central nervous system negative acute lymphoblastic leukemia (ALL) in August 1997. He was treated with a high-risk acute lymphoblastic leukemia protocol Children's Cancer Group (CCG-1882), secondary to unfavorable cytogenetics. He achieved complete remission with induction treatment consisting of weekly intravenous vincristine, daunomycin, daily oral prednisone, and nine doses of intramuscular L-asparginase. Consolidation consisted of cranial irradiation, 1800 cGy in 12 fractions of 150 cGy each, four doses of intrathecal MTX, intravenous Cytoxan and cytarabine. Prior to start of maintenance, he received reinduction/ reconsolidation treatment along with two doses of intrathecal methtrexate. Maintenance consisted of monthly pulses of intravenous vincristine, oral prednisone, weekly oral MTX and daily oral 6-merceptopurine, with intrathecal MTX every 3 months. He was admitted as an emergency, 14 days after the last intrathecal MTX in May 1999, with left focal seizures approximately 20 months after diagnosis. He had received atotal dose of 156 mg MTX intrathecally. A computerized tomography (CT) scan of the brain on the 27th of May revealed bilateral symmetrical periventricular hypodence white matter changes in the frontoparietal region. There were no calcifications orintracranial bleeding (Figure 1). Magnetic resonance imaging (MRI) on the 30 th of May revealed multiple high intensity areas in the subcortical and periventricular white matter on fluid attenuated inversion recovery (FLAIR) imaging representing leukoencephalopathy (Figure 2). Seizures were aborted with lorazepam, and patient was discharged on carbamezapine. Two weeks later, he was readmitted because he had changed from a talkative boy of superior intelligence into a child that only answered questions with strong stimulation. He was also having seizures. A repeat MRI on the 27th of June, four weeks after the first MRI, revealed stable diffuse white matter changes described previously, but with emergence of bilateral cortical changes in the parietooccipital lobes, with more on the right, probably representing cortical edema (Figure 3A). These cortical changes were more readily apparent on FLAIR sequence (Figure 3B). Lumbar puncture ruled out central nervous system relapse and infectious etiology as a cause of rapid deterioration. Cerebrospinal fluid analysis for myelin basic proteins, and polymerase chain reaction for herpes simplex virus were both negative.

Leukoencephalopathy and Cortical Laminar Necrosis Associated with Intrathecal Methotrexate and Cranial Irradiation

Figure 1. Axial contrast enhanced CT of the brain taken on May 27, 1999, showing bilateral symetricalperiventicularhypodence white matter changes in the frontoparietal region.

Figure 2. Flair image. Coronal view taken on 30 May 99, showing multiple high intensity areas in the subcortical and periventricular white matter representing leukoencephalopathy.

Over the next few days, he devolved into a state of akinetic mutism, and developed stereotyped yawning, weeping, moaning, facial twitching and loss of initiative. Spontaneousspeech was almost absent. Neurological examination showed diminished facial expression, spontaneous eye blinking and bilateral pyramidal paresis, seen more on the left side. His seizures were difficult to control despite multiple trials of anticonvulsants that included phenytoin, phenobarbitone and clobazam. The electroencephalogram (EEG) showed diffuse background slowing consistent with global encephalopathy. A follow-up MRI on the 10th of August showed progressive white matter changes in the periventricular area, severe cortical involvement in the frontal, temporal, parietal, and occipital lobes along with the emergence of bright, new signals in basal ganglia on both sides on T2-weighted neuroimaging (Figure 4A) representing progressive ischemic changes, while Tl-weighted imaging revealed curvilinear, cortical hyperintense lesions in the frontal, parietal, temporal and occipital cortex characteristic of cortical laminar necrosis (Figure 5). These findings, conducted close to his death, contrasted sharply with the MRI neuroimaging on the 14th of June which had only showed subtle involvement of cortex and normal appearing basal ganglia (Figure 4B). He remained in this condition for 10-12 weeks and finally died of overwhelming E.coli sepsis. A brain biopsy was refused. Discussion We describe a unique case of delayed necrotizing leukoencephalopathy (DNL), in which akinetic mutism was predominant symptom. Akinetic mutism, an extreme form of a frontal syndrome, may result from lesions affecting the reticulo-cortical or limbic-cortical integration.2-4 Three types of frontal syndromes are recognized, the dorsolateral frontal syndrome, the orbitofrontal syndrome and the anterior cingulate syndrome. 5 Anterior cingulate syndrome is characterized by apathetic behavior and severe loss of initiative. These patients show no emotion, do not eat or drink on being fed, and do not speak spontaneously. In the present case, all symptoms of anterior cingulate syndrome as described by Cumming's were present and deteriorated to the extreme a state of akineticmutism. 3 Delayed necrotizing leukoencephalopathy, a complication of leukemia treatment, may occur after

Annals of Saudi Medicine, Vol 23 No. 3-4; 2003

Leukoencephalopathy and Cortical Laminar Necrosis Associated with Intrathecal Methotrexate and Cranial Irradiation

intrathecal,1intraventricular,7 or high-dose intravenous treatment with MTX8 in combination with 5-fluorouracil and is seen mostly in patients who have received concomitant cranial irradiation. 8 The exact mechanism of MTX-induced neurotoxicity remains unclear. It is likely multifactorial. Chronic folate depletion of the brain tissue, relative homocysteine excess with increased excitatory amino acids, and alteration of adenosine metabolism have been proposed as possible mechanisms for some acute and chronic neurotoxicities. 12 It has also been proposed that chronic MTX exposure leads to an increase in plasma and cerebrospinal concentration ofhomocysteine, which increases the risk for vascular endothelial damage. Vascular endothelial damage may be an important essential step in the development of delayed MTX neurotoxicity,12 and along with the additional damaging effects of irradiation upon the vascular endothelium, may cause DNL. 5 The clinical diagnosis of delayed necrotizing leukoencephalopathy is supported by the CT and MR findings of periventricular hypodensities in our case. Cortical laminar necrosis (CLN), a condition resulting from cerebral energy depletion, was another feature of this case. To our knowledge it has never been reported as a complication of leukemia treatment. CLN was originally a histopathological entity but with the advent of MR imaging, it has become an MR imaging diagnosis, due to peculiar imaging findings. The MR diagnosis of CLN is based on the T1-weighted imaging findings, with cortical hyperintensity in the involved areas appearing approximately 2-3 weeks after the onset of insult, which is usually hypoxia. The brain requires a continuous supply of oxygen and glucose for metabolic needs. Normally, about 90% of this energy is obtained from the oxidative metabolism of glucose, reflecting the inability of the brain to utilize other substrates for energy. As neither glucose nor oxygen is stored in the brain, the organ is susceptible to a deficiency of either. Neurons are more vulnerable to oxygen and glucose deficiencies than are the oligodendrocytes and astrocytes, while microglia and blood vessels are least vulnerable. If structural damage after an episode of oxygen or glucose deprivation is limited to neurons, a process called selective neuronal necrosis entails. 6In severe cases of energy depletion, where blood vessels, nerve fibers and glia are implicated, an infarct will result. Selective neuron necrosis may involve different parts of the brain, such as the basal ganglia, thalamus, brainstem, cerebral cortex and cerebellar cortex. Within the cerebral cortex, selective neuronal necrosis is usually more prominent in the deeper layers. More severe lesions involve all the cortical layers. Conditions that result in energy deprivation are diverse. Hypoxia in respiratory diseases, reduced blood flow to the brain with cardiac problems and severe hypogylcemia are examples. As mentioned, CLN can occur in states of consumptive energy depletion such as in status epilecticus when energy requirements of hyperactive neurons exceed the available supply of neutrients.10,11,13 The development of transient neurological dysfunction, characterized by hemiparesis, facial nerve weakness, speech disturbance, seizures, and an altered level of consciousness in patients who have been treated with high dose intravenous MTX (dose>8-10 g/m2) with citovorin rescue is well established, with several previously described cases.14,15However, no CT or MRI evidence of ischemic insultcorrelating with neurologic manifestation was documented in these cases. In contrast, Yim et al described three patients with transient hemiparesis and dysarthria after administration of intrathecal MTX alone, or as triple intrathecal therapy, during the course of maintenance therapy. Ischemic lesions corresponding anatomically with the patient's neurologic complication were detected by CT or MRI examination. None of the three patients had received irradiation therapy. 16Similarly DiMario and Packer reported stroke syndromes in 4 of 31 children with ALL presenting with acute mental state changes during the course of therapy.17 No neuroimaging studies were performed in those cases. Barggalloet al. described three patients who developed cortical laminar necrosis after immunosuppresive treatment (cyclosporin A and FK 506) and polychemotherapy (vincristine and MTX). None of the three patients had received irradiation therapy,16(FK 506) and polychemotherapy (vincristine and MTX).18 The neuroradiologic findings suggested a transient hypoxic pathogenesis.

Annals of Saudi Medicine, Vol 23 No. 3-4; 2003

Leukoencephalopathy and Cortical Laminar Necrosis Associated with Intrathecal Methotrexate and Cranial Irradiation

Figure 3.(A) T2 weighted axial image, taken on June 27, 1999, showing cortical hyperintense changes involving the parieto-occipital lobes bilaterally, more on right side representing focal cortical edema along with white matter changes. (B) Flair image, coronal view, taken on 27 June 1999, showing hyperintense cortical changes in the temporal and frontal region, more on the right side, along with subcortical and periventricualr white matter changes.

Figure 4.(A) T2 weighted axial image, taken on August 10, 1999, showing severe involvement of cortex in the frontal, temporal, and parieto-occipital region along with subcortical and periventricular white matter changes. Note the involvement of basal ganglia on both sides. (B) T2weighted axial image, taken on 14 June 1999, showing only subtle cortical involvement and normal appearing basal ganglia.

Figure 5.T1 weighted axial image, taken on August 10, 1999, showing curvilinear cortical hyperintense lesions in the frontal, parietal and occipitalcortex representing cortical laminar necrosis

Our patient suffered a catastrophic series of neurologic events late in the course of ALL treatment. The clinical picture described is an unusual but recognized presentation, consistent with late leukoencephalopathy following

Annals of Saudi Medicine, Vol 23 No. 3-4; 2003

Leukoencephalopathy and Cortical Laminar Necrosis Associated with Intrathecal Methotrexate and Cranial Irradiation

treatment with cranial irradiation and repeated doses of intrathecal MTX. Subsequent neurological deterioration, consisting of CLN, which is well depicted on serial neuroimaging with a characteristic T1-weighted neuroimaging finding, presumably had occurred in the setting of difficult-to-control seizures, leading to transient cerebral ischemia (seizure related phenomena). This seems more likely than a direct toxic effect of CNS therapy. To our knowledge, this is the first reported case of pure MTX-related CLN. Perhaps the combination of MTX, along with cranial irradiation, can result in increased neurotoxic effects. References 1. Mahoney DH, Shuster JJ, Nitschke R, Lauer SJ, Steuber P, Winick N, and Camitta B, et al. Acute Neurotoxicity in Children With B-Precursor Acute Lymphoid Leukemia: An Association With Intermediate-Dose Intravenous Methotrexate and Intrathecal Triple Therapy. A POG Study: J Clin Oncol 1998;16;1712-22. 2. Plum F, Posner JB. The diagnosis of stuper and coma. 1998. Davis, Philadelphia. 3. Cummings JL. Frontal-subcortical ciruits in human behavior. Arch Neorol 1993;50:873-80. 4. Van Mourik M, Van Dongen HR, Catsman-Berrevoets CE. The many faces of acquired neurologic mutism in childhood. Pediatr Neurol 1997(in press). 5. Gutling E, Landis T, Kleihues P. Akinetic mutism in bilateral necrotizing leuco-encephalopathy; electrophysiological and autopsy findings. J Neurol 1992;239:125-8. 6. Araki, TH Kato, K Kogure. Selective neuronal vulnerability following transient cerebral ischemia in the gernil: distribution and time course. Acta Neurol Scand 1989;80:548-53. 7. Shapiro WR, Chernik NL, Posner JB. Necrotizing encephalopathy following the intraventicular instillation of methotrexate. Arch Neurol 1973;28:96-102. 8. Rubestein LJ, Herman MM,Long TF, Wilbur JR. Disseminated necrotizing leukoencephalopathy: a complication of treated central nervous system leukemia and lymphoma. Cancer 1975;35:291-305. 9. Medldrum BS: Metabolic effects of prolonged epileptic seizures and the causation of epileptic brain damage. Rose, F.C.(Ed) Metabolic disorders of Central Nervous System. London, Pitman 1981;175-87. 10. Graham Dl. Hypoxia and vascular disorders. Greenfield's Neuropathology, 5th ed. London. Edward Arnold, 1992;153-268. 11. Auer RN. Progress review: hypoglycemic brain damage. Stroke 1986;17:699-708. 12. Quinn CT, Griener JC, Bottiglieri T, et.al. Elevation of homocysteine and excitatory aminoacid neurotransmitters in the CSF of children who receive methotrexate for the treatment of cancer. J Clin Oncol 1997;15:2800-6. 13. Medldrum BS. Metabolic effects of prolonged epileptic seizures and the causation of epileptic brain damage. Rose, F.C. (Ed) Metabolic disorders of central nervous system. London, Pitman. 1981;175-87. 14. Jaffe N, Takaue Y, Anazi T, Robertson R. Transient neurologic disturbances induced by high-dose methotrexate treatment. Cancer 1985;56:1356-60. 15. Martino RL, Benson AB, Merritt JA, et.al. Transient neurologic dysfunction following moderate-dose methotrexate for undifferentiated lymphoma. Cancer 1984;54:2003-5. 16. Yim Y, et.al. Hemiparesis and ischemic changes of the white matter after intrathecal therapy for children with acute lymphoblastic leukemia. Cancer 1991;15:2058-61. 17. DiMario FJ, Packer RJ. Acute mental state changes in children with systemic cancer. Pediatrics 1990;85:353-60. 18. Bargalla N, Burrel M, Berenguer J, et.al. Cortical laminar necrosis caused by immunosuppressive therapy and chemotherapy. Am J Neuroradiol 2000;21:479-84.

Annals of Saudi Medicine, Vol 23 No. 3-4; 2003

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