Abstract
Three children with acute lymphoblastic leukemia developed altered mental status, headaches, seizures, and visual changes associated with reversible posterior cerebral changes on MRI. These clinical and radiologic findings were consistent with the reversible posterior leukoencephalopathy syndrome, which has not been widely recognized in this setting.
In 1996, Hinchey et al. coined the term “reversible posterior leukoencephalopathy” to describe a syndrome of headaches, confusion, seizures, and visual disturbances associated with transient, predominantly posterior lesions on neuroimaging.1 The reversible posterior leukoencephalopathy syndrome (RPLS) occurs in both children and adults in association with hypertension and/or immunosuppression.2 Known triggers include acute renal failure, eclampsia (especially puerperal), and the use of cyclosporine, FK506, or interferon-α.1 As RPLS has become better recognized, additional contributing factors have been identified. For example, reports have linked RPLS to the use of erythropoietin in end-stage renal disease, cancer treatment with cisplatin, and porphyria.3-5⇓⇓
We describe three children who developed RPLS during the treatment of acute lymphoblastic leukemia (ALL).
Patient 1.
An 8-year-old girl was diagnosed with standard-risk ALL. Induction was completed, and consolidation with intrathecal methotrexate was initiated on day 28/0, according to Children’s Cancer Group study protocol (CCG) 1962.
Two days later, she presented with hematuria and abdominal pain secondary to kidney stones. Later that day, she became acutely but transiently unresponsive with an elevated blood pressure of 154/95 mm Hg (from a baseline of 107/61 mm Hg). MRI demonstrated heterogeneously enhancing posterior parieto-occipital lesions, predominantly in the white matter and at the gray-white junction. These lesions were best visualized on T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences. MR arteriography and MR venography were normal. Her serum magnesium level was 1.6 mg/dL. Her elevated blood pressure was treated with low-dose nifedipine (0.175 mg/kg).
The patient’s mental status remained abnormal, with waxing and waning disorientation. She also had “blurry vision,” headaches, and eye pain. Three days later, she again became acutely unresponsive with respiratory failure, requiring intubation. Two episodes of eye deviation were noted. Her blood pressure was again elevated at 140/90 mm Hg, and her serum magnesium level had dropped to 0.9 mg/dL. Repeat MRI showed an increase in the size of the parieto-occipital lesions with increased diffusion but less enhancement ( figure 1A). She received phenytoin, nifedipine, and magnesium sulfate.
Figure 1. Patient 1. (A) Axial fluid-attenuated inversion recovery MR sequence of the brain demonstrates bilateral posterior parieto-occipital white matter abnormalities in addition to left frontal T2-weighted bright signal abnormality. (B) A follow-up scan 1 month later shows almost complete resolution of the abnormalities.
She recovered rapidly and was extubated the next day, but seemed to be hallucinating. A neuro-ophthalmologic examination documented cortical blindness, which slowly resolved over the next week. Subsequent magnesium levels ranged from 1.2 to 1.7 mg/dL. Intrathecal therapy (consolidation) resumed 10 days after her last seizure. She received a total of four subsequent doses of intrathecal methotrexate without incident. Follow-up MRI 1 month later, at which time she was clinically normal, was significantly improved, though there was some minimal residual nonenhancing abnormal T1- and T2-weighted signal in the left posterior and right anterior parietal lobes (figure 1B). The patient remained seizure-free, and phenytoin was discontinued after 3 months.
Patient 2.
A 9-year-old girl was diagnosed with standard-risk T-cell ALL after presenting with a superior vena caval compression syndrome. She received one dose of mediastinal radiation and began chemotherapy.
On day 19 of induction (CCG 1952), she had a 2-minute generalized convulsion. MRI showed nonenhancing T2-weighted and FLAIR signal abnormalities in bilateral parietal and right temporo-occipital regions. Diffusion-weighted imaging was normal. Her blood pressures ranged from 113/81 to 129/90 mm Hg. Her magnesium level was 2.1 mg/dL. No anticonvulsant medications were given.
The patient recovered and was in complete remission when induction was completed, and consolidation was initiated on day 27/0 with intrathecal methotrexate and intravenous vincristine. Three days later, she became lethargic and then had five generalized tonic-clonic seizures. She received diazepam, lorazepam and intravenous phenytoin.
Repeat MRI demonstrated a new right parietal lesion, resolution of the old right parietal lesion but an increase in the size of the left parietal abnormality, and a new left frontal lesion on T2-weighted and FLAIR sequences. MR venography was normal. No visual complaints were noted, though she did complain of a mild headache.
Although no elevated blood pressures were documented at the time of her seizures (maximum 118/78 mm Hg), subsequent blood pressures ranged from 104/59 to 144/92 mm Hg. No antihypertensive therapy was given. Daily serum magnesium levels ranged from 1.9 to 2.1 mg/dL.
Intrathecal therapy was delayed for 1 week; then consolidation and intensive maintenance therapy resumed without incident. Follow-up MRI 1 month later showed complete resolution of all the gray-white lesions. She remained on phenytoin for 1 year but had no subsequent seizures.
Patient 3.
An 11-year-old boy was diagnosed with high-risk ALL. He responded completely by day 12 of induction (CCG 1961) but was admitted on day 25 with abdominal pain and vomiting secondary to pancreatitis. He had pre-existing hypertension that was being treated with amlodipine.
Induction was completed in the hospital, and consolidation was initiated on day 28/0 with intrathecal methotrexate. His blood pressure was markedly elevated that day at 155/93 mm Hg (compared with baseline pressures between 90/60 and 115/71 mm Hg). The next day, he had two generalized tonic-clonic convulsions, preceded by head turning to the right. MRI showed bilateral parieto-occipital enhancing lesions involving both cortex and subcortex, which were best visualized on T2-weighted and FLAIR images ( figure 2). Increased diffusion was seen in these regions. MR venography was normal. His serum magnesium level was 2.1 mg/dL. The seizures were treated with lorazepam and phenytoin. His amlodipine dose remained unchanged.
Figure 2. Patient 3. Axial fluid-attenuated inversion recovery MR sequence of the brain demonstrates bilateral parieto-occipital signal abnormalities involving both cortex and subcortical white matter.
The patient’s blood pressures subsequently ranged from 126/67 to 145/88 mm Hg. For 2 days after his seizures, he was lethargic and had difficulty visually fixing and following, complaining of “blurred vision” and “trouble seeing.” This cleared rapidly on the third day, however, and a subsequent neuro-ophthalmologic exam was essentially normal. His next dose of intrathecal methotrexate was held, but otherwise consolidation proceeded without complication. He remained seizure-free for 3 months, and the phenytoin was stopped.
Discussion.
The cardinal features of RPLS are both clinical and radiologic. In the description of RPLS by Hinchey et al.,1 altered mental status, headaches, seizures, and visual disturbances were prominent. In a survey of the pediatric literature, 76% of children with RPLS had at least three of these four signs.2 Hypertension is commonly associated with RPLS but may be relatively mild and is not universally present, especially in the setting of immunosuppression.1,6⇓
On neuroimaging, the posterior parts of the cerebrum, especially the parieto-occipital regions, are generally involved, with relative sparing of the occipital cortex.1 The frontal lobes, cerebellum, and brainstem may also be involved.1,6,7⇓⇓ MR abnormalities are characterized by increased signal on T2-weighted and FLAIR sequences. Diffusion-weighted imaging can be normal or may demonstrate increased diffusion consistent with vasogenic edema.6,7⇓ Contrast enhancement is variable and consistent with transient breakdown of the blood-brain barrier.1,7⇓
It is believed that the transient radiologic lesions in RPLS represent a failure of the autoregulatory capabilities of the cerebral vessels. This leads to hyperperfusion breakdown of the blood-brain barrier and consequent vasogenic edema.6,7⇓ The preferential involvement of the parietal and occipital lobes is hypothesized to be related to the observed relative reduction in the sympathetic innervation of the posterior circulation.1,7⇓ Presumably, this hyperperfusion may be triggered by hypertension or seizures or both.7 Drugs have been postulated to contribute to this physiologic effect by direct cytotoxic effects, by inducing/exacerbating hypertension, or by lowering the seizure threshold.1,6⇓ Hypomagnesemia may also be a contributing factor.1
Each of our patients had at least three of the cardinal clinical signs of RPLS in addition to posterior cerebral MR changes consistent with vasogenic edema (T2-weighted/FLAIR signal abnormalities, increased diffusion, and variable enhancement). In our first two patients, the lesions reversed within 1 month. The third patient has not yet been reimaged. Hypertension was noted in all three of our patients. Hypomagnesemia was seen only in one. All three children have done well subsequently, completing their chemotheraputic regimens without further occurrences of seizures or RPLS. Treatment was primarily supportive, though both antihypertensive and anticonvulsant medications were given. Each child received further chemotherapy without recurrence of RPLS.
Our patients developed RPLS during or shortly after induction chemotherapy for ALL. The induction protocols CCG 1962, 1952, and 1961 are similar. Each child received daily prednisone for 28 days, l-asparaginase every other day (nine doses), intrathecal cytarabine (one dose, day 0), weekly vincristine (four or five doses), and intrathecal methotrexate (two doses, days 8 and 28). Patient 3 also received weekly daunomycin (four doses). Though there appears to be a link between these drugs and RPLS in the setting of ALL, it is difficult to establish exactly which drug or combination of drugs is responsible. It is perhaps suggestive that three of the four clinical “episodes” of RPLS occurred at the end of induction, days after administration of a second dose of intrathecal methotrexate, but a complex interaction between the various chemotheraputic agents and the children’s malignancy cannot be ruled out.
Before 1996, seizures and transient neurologic disturbances such as visual hallucinations and confusion were reported in association with reversible, predominantly posterior, radiologic lesions following administration of chemotheraputic agents but were not recognized as RPLS.8-10⇓⇓ These reports blamed methotrexate (intravenous and intrathecal),8 the combination of prednisone and vincristine,9 or high-dose intravenous cytarabine10 for the syndrome. As in our cases, however, these reports were confounded by the administration of multiple agents and concurrent immunosuppression and hypertension, making it difficult to establish a causal link between these presentations and any one particular agent or combination of agents.
Chemotherapy for ALL should be added to the growing list of causes of RPLS, but more information will be needed before a clear connection can be established between RPLS and a specific agent(s). Considering RPLS in this setting may prevent overly aggressive management following a mistaken diagnosis of chemonecrosis, progressive multifocal leukoencephalopathy, demyelination, or infarction.7
Acknowledgments
Acknowledgment
The authors thank Dr. Beverly Lange for her helpful comments during the preparation of the manuscript.
- Received July 21, 2000.
- Accepted October 2, 2000.
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