Brief Communication Journal of Child Neurology 1-3 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073814538501 jcn.sagepub.com
Late-Onset Radiation-Induced Vasculopathy and Stroke in a Child With Medulloblastoma Lalit R. Bansal, MD1, Jeffrey Belair, MD2, Dana Cummings, MD, PhD1, and Giulio Zuccoli, MD2
Abstract We report a case of a 15-year-old boy who presented to our institution with left-sided weakness and slurred speech. He had a history of medulloblastoma diagnosed at 3 years of age, status postsurgical resection and craniospinal radiation. Magnetic resonance imaging (MRI) of brain revealed a right paramedian pontine infarction, suspected secondary to late-onset radiationinduced vasculopathy of the vertebrobasilar system. Radiation to the brain is associated with increased incidence of ischemic stroke. Clinicians should have a high index of suspicion for stroke when these patients present with new neurologic symptoms. Keywords vasculopathy, radiation, brain tumor Received January 30, 2014. Received revised April 17, 2014. Accepted for publication May 07, 2014.
Case Summary A 15-year-old, right-handed, boy presented to our institution in August 2012 with a 1-day history of left-sided weakness and slurred speech. His medical history was remarkable for medulloblastoma diagnosed at 3 years of age with total resection and craniospinal radiation of 2340 cGy and a 5580 cGy boost to the posterior fossa. He also received adjuvant chemotherapy with cisplatin and lomustine. Additional history included hydrocephalous, requiring ventriculoperitoneal shunt, chronic headaches, obesity, type 2 diabetes mellitus, hypertension, and hypothyroidism. One day prior to presentation, the patient awoke from sleep with left arm weakness. An hour later, weakness spread to his left leg. Symptoms persisted the next morning and family members noticed slurred speech and left facial droop. Initial evaluation at an outside hospital revealed elevated blood pressure of 160/100 mm Hg. Ventriculoperitoneal shunt series and noncontrast head computed tomography showed no acute pathology. He was subsequently transferred to our children’s hospital for further evaluation and management. On physical examination, blood pressure remained elevated at 160/100 mm Hg. He was awake, alert, and oriented to time, place, and person. Speech was slurred but he was able to follow commands and express appropriate verbal responses. Pupils were equal and reactive with intact gaze. Facial asymmetry was seen, with right lower facial weakness. Muscle tone was normal, but he had left hemiparesis, with the arm affected more
than the leg, more prominent in distal muscle groups. Deep tendon reflexes were easy to elicit but Babinski reflex was present on the left. Laboratory workup showed normal complete blood count, prothrombin time and partial thromboplastin time. Brain magnetic resonance imaging (MRI) and magnetic resonance angiography were performed. Diffusion-weighted images revealed restricted diffusion in the right paramedian pons, consistent with acute-subacute infarction (Figure 1A, B). Magnetic resonance angiography images revealed luminal irregularity of both intradural vertebral arteries and basilar trunk without occlusion (Figure 1C). Our presumptive diagnosis was pontine infarction secondary to late-onset radiation-induced vasculopathy. His stroke risk factor workup showed normal hemoglobin A1c and elevated low-density lipoprotein at 156 mg/dL. Echocardiogram was unremarkable. His obesity, hypertension, hyperlipidemia, and glucose intolerance were considered likely contributing factors. Given his high risk of stroke recurrence in
1
Division of Child Neurology, Children’s Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA, USA 2 Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA Corresponding Author: Lalit R. Bansal, MD, Division of Child Neurology, Children’s Hospital of Pittsburgh of University of Pittsburgh Medical Center, 4401 Penn Ave, Faculty Pavilion 8th Floor, Pittsburgh, PA 15224, USA. Email: [email protected]
Downloaded from jcn.sagepub.com at MEMORIAL UNIV OF NEWFOUNDLAND on December 12, 2014
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Journal of Child Neurology
Figure 1. Diffusion-weighted image and apparent coefficient diffusion map images demonstrate true restricted diffusion predominantly involving the right pons (arrows, A, B). Magnetic resonance angiography maximum-intensity projection images of the combined anterior and posterior circulation demonstrate fusiform dilatations and narrowing of the vertebral and basilar arteries (arrows, C).
the setting of radiation-induced vasculopathy and hyperlipidemia, he was started on aspirin, vitamin E, and simvastatin. His neurologic examination showed marked improvement over the next month. At 19 months follow-up, his left hemiparesis has markedly improved with residual minimal upper and lower extremity weakness.
Discussion Stroke is rare in children, with an annual incidence of 2.3 to 13 per 100,000 children. It is increasingly recognized as an important cause of morbidity and mortality in children. There is often a poor prognosis and high risk of recurrence.1 Numerous risk factors for pediatric stroke have been identified, including arteriopathies, vascular malformations, and hematologic and metabolic disorders.2 In one retrospective analysis of pediatric patients with primary brain neoplasms, authors reported a 100-fold increase in risk of transient ischemic attack or stroke compared to the general population. Of 431 subjects with brain tumors, 14 had cerebrovascular events. Thirteen of these 14 patients had received radiation therapy. The median duration
to stroke from initial radiation was 4.9 years. Radiation to the circle of Willis was specifically associated with increased stroke risk (hazard ratio 4.35).3 The Childhood Cancer Survival Study, a multi-institutional retrospective cohort study of 14,358 5-year survivors of childhood cancers, has also shown an increase rate of stroke in this population. Age-adjusted stroke rate was 77 per 100,000 (95% cumulative incidence 62-96), compared to 9.3 (95% cumulative incidence 4-23) for siblings, and treatment with cranial radiation therapy increased stroke risk in a dose-dependent manner.4 Cumulative incidence of risk for recurrence of stroke in patients who received cranial radiation therapy is also high and has been reported as 20% (95% cumulative incidence: 7%-50%) at 1 year after first stroke and 38% (95% cumulative incidence: 17%-69%) at 5 years.5 High blood pressure, raised low-density lipoprotein, and hypercholesterolemia, which are independent risk factors for stroke in adults, are rare in children. Cranial radiation therapy is significantly associated with increased incidence of obesity, raised blood pressure, hypercholesterolemia, and dyslipidemia in childhood brain tumor survivors.6 Case reports have described delayed postirradiation vasculopathy in children with treated medulloblastoma, with similar radiologic findings including arterial wall irregularities and focal stenoses.7 Our patient’s presentation with stroke symptoms and imaging findings resembling lacunar syndromes commonly seen in older adults suggest that radiation combined with other risk factors (hypertension, hyperlipidemia, diabetes and/or obesity) might accelerate the pathogenesis of small vessel disease. In children with history of brain tumor treated with radiation, identifying those at risk for delayed cerebrovascular complications is an important task. Measures to minimize radiation to the posterior fossa during treatment could potentially decrease long-term risk of radiation-induced vasculopathy and stroke in brain tumor survivors. Authors’ Note This work was done at the Children’s Hospital of Pittsburgh of University of Pittsburgh Medical Center.
Author Contributions LRB and JB performed literature search and drafted the manuscript. LRB revised the manuscript and along with DC took care of the patient. GZ described the radiologic findings. DC and GZ reviewed the manuscript.
Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The authors received no financial support for the research, authorship, and/or publication of this article.
Ethical Approval Departmental policy does not require ethical approval for case reports in which the patient’s anonymity is preserved.
Downloaded from jcn.sagepub.com at MEMORIAL UNIV OF NEWFOUNDLAND on December 12, 2014
Bansal et al
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References 1. Amlie-Lefond C, Se´bire G, Fullerton HJ. Recent developments in childhood arterial ischaemic stroke. Lancet Neurol. 2008;7:425-435. 2. Lanthier S, Carmant L, David M, Larbrisseau A, deVeber G. Stroke in children: the coexistence of multiple risk factors predicts poor outcome. Neurology. 2000;54:371-378. 3. Campen CJ, Kranick SM, Kasner SE, et al. Cranial irradiation increases risk of stroke in pediatric brain tumor survivors. Stroke. 2012;43:3035-3040. 4. Mueller S, Fullerton HJ, Stratton K, et al. Radiation, atherosclerotic risk factors, and stroke risk in survivors of pediatric cancer: a report
from the Childhood Cancer Survivor Study. Int J Radiat Oncol Biol Phys. 2013;86:649-655. 5. Mueller S, Sear K, Hills NK, et al. Risk of first and recurrent stroke in childhood cancer survivors treated with cranial and cervical radiation therapy. Int J Radiat Oncol Biol Phys.2013;86:643-648. 6. Pietila¨ S, Ma¨kipernaa A, Sieva¨nen H, et al. Obesity and metabolic changes are common in young childhood brain tumor survivors. Pediatr Blood Cancer. 2009;52:853-859. 7. Grenier Y, Tomita T, Marymont MH, Byrd S, Burrowes DM. Late postirradiation occlusive vasculopathy in childhood medulloblastoma—report of two cases. J Neurosurg. 1998;89:460-464.
Downloaded from jcn.sagepub.com at MEMORIAL UNIV OF NEWFOUNDLAND on December 12, 2014
Late-Onset Radiation-Induced Vasculopathy and Stroke in a Child With Medulloblastoma Lalit R. Bansal, MD1, Jeffrey Belair, MD2, Dana Cummings, MD, PhD1, and Giulio Zuccoli, MD2
Abstract We report a case of a 15-year-old boy who presented to our institution with left-sided weakness and slurred speech. He had a history of medulloblastoma diagnosed at 3 years of age, status postsurgical resection and craniospinal radiation. Magnetic resonance imaging (MRI) of brain revealed a right paramedian pontine infarction, suspected secondary to late-onset radiationinduced vasculopathy of the vertebrobasilar system. Radiation to the brain is associated with increased incidence of ischemic stroke. Clinicians should have a high index of suspicion for stroke when these patients present with new neurologic symptoms. Keywords vasculopathy, radiation, brain tumor Received January 30, 2014. Received revised April 17, 2014. Accepted for publication May 07, 2014.
Case Summary A 15-year-old, right-handed, boy presented to our institution in August 2012 with a 1-day history of left-sided weakness and slurred speech. His medical history was remarkable for medulloblastoma diagnosed at 3 years of age with total resection and craniospinal radiation of 2340 cGy and a 5580 cGy boost to the posterior fossa. He also received adjuvant chemotherapy with cisplatin and lomustine. Additional history included hydrocephalous, requiring ventriculoperitoneal shunt, chronic headaches, obesity, type 2 diabetes mellitus, hypertension, and hypothyroidism. One day prior to presentation, the patient awoke from sleep with left arm weakness. An hour later, weakness spread to his left leg. Symptoms persisted the next morning and family members noticed slurred speech and left facial droop. Initial evaluation at an outside hospital revealed elevated blood pressure of 160/100 mm Hg. Ventriculoperitoneal shunt series and noncontrast head computed tomography showed no acute pathology. He was subsequently transferred to our children’s hospital for further evaluation and management. On physical examination, blood pressure remained elevated at 160/100 mm Hg. He was awake, alert, and oriented to time, place, and person. Speech was slurred but he was able to follow commands and express appropriate verbal responses. Pupils were equal and reactive with intact gaze. Facial asymmetry was seen, with right lower facial weakness. Muscle tone was normal, but he had left hemiparesis, with the arm affected more
than the leg, more prominent in distal muscle groups. Deep tendon reflexes were easy to elicit but Babinski reflex was present on the left. Laboratory workup showed normal complete blood count, prothrombin time and partial thromboplastin time. Brain magnetic resonance imaging (MRI) and magnetic resonance angiography were performed. Diffusion-weighted images revealed restricted diffusion in the right paramedian pons, consistent with acute-subacute infarction (Figure 1A, B). Magnetic resonance angiography images revealed luminal irregularity of both intradural vertebral arteries and basilar trunk without occlusion (Figure 1C). Our presumptive diagnosis was pontine infarction secondary to late-onset radiation-induced vasculopathy. His stroke risk factor workup showed normal hemoglobin A1c and elevated low-density lipoprotein at 156 mg/dL. Echocardiogram was unremarkable. His obesity, hypertension, hyperlipidemia, and glucose intolerance were considered likely contributing factors. Given his high risk of stroke recurrence in
1
Division of Child Neurology, Children’s Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA, USA 2 Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA Corresponding Author: Lalit R. Bansal, MD, Division of Child Neurology, Children’s Hospital of Pittsburgh of University of Pittsburgh Medical Center, 4401 Penn Ave, Faculty Pavilion 8th Floor, Pittsburgh, PA 15224, USA. Email: [email protected]
Downloaded from jcn.sagepub.com at MEMORIAL UNIV OF NEWFOUNDLAND on December 12, 2014
2
Journal of Child Neurology
Figure 1. Diffusion-weighted image and apparent coefficient diffusion map images demonstrate true restricted diffusion predominantly involving the right pons (arrows, A, B). Magnetic resonance angiography maximum-intensity projection images of the combined anterior and posterior circulation demonstrate fusiform dilatations and narrowing of the vertebral and basilar arteries (arrows, C).
the setting of radiation-induced vasculopathy and hyperlipidemia, he was started on aspirin, vitamin E, and simvastatin. His neurologic examination showed marked improvement over the next month. At 19 months follow-up, his left hemiparesis has markedly improved with residual minimal upper and lower extremity weakness.
Discussion Stroke is rare in children, with an annual incidence of 2.3 to 13 per 100,000 children. It is increasingly recognized as an important cause of morbidity and mortality in children. There is often a poor prognosis and high risk of recurrence.1 Numerous risk factors for pediatric stroke have been identified, including arteriopathies, vascular malformations, and hematologic and metabolic disorders.2 In one retrospective analysis of pediatric patients with primary brain neoplasms, authors reported a 100-fold increase in risk of transient ischemic attack or stroke compared to the general population. Of 431 subjects with brain tumors, 14 had cerebrovascular events. Thirteen of these 14 patients had received radiation therapy. The median duration
to stroke from initial radiation was 4.9 years. Radiation to the circle of Willis was specifically associated with increased stroke risk (hazard ratio 4.35).3 The Childhood Cancer Survival Study, a multi-institutional retrospective cohort study of 14,358 5-year survivors of childhood cancers, has also shown an increase rate of stroke in this population. Age-adjusted stroke rate was 77 per 100,000 (95% cumulative incidence 62-96), compared to 9.3 (95% cumulative incidence 4-23) for siblings, and treatment with cranial radiation therapy increased stroke risk in a dose-dependent manner.4 Cumulative incidence of risk for recurrence of stroke in patients who received cranial radiation therapy is also high and has been reported as 20% (95% cumulative incidence: 7%-50%) at 1 year after first stroke and 38% (95% cumulative incidence: 17%-69%) at 5 years.5 High blood pressure, raised low-density lipoprotein, and hypercholesterolemia, which are independent risk factors for stroke in adults, are rare in children. Cranial radiation therapy is significantly associated with increased incidence of obesity, raised blood pressure, hypercholesterolemia, and dyslipidemia in childhood brain tumor survivors.6 Case reports have described delayed postirradiation vasculopathy in children with treated medulloblastoma, with similar radiologic findings including arterial wall irregularities and focal stenoses.7 Our patient’s presentation with stroke symptoms and imaging findings resembling lacunar syndromes commonly seen in older adults suggest that radiation combined with other risk factors (hypertension, hyperlipidemia, diabetes and/or obesity) might accelerate the pathogenesis of small vessel disease. In children with history of brain tumor treated with radiation, identifying those at risk for delayed cerebrovascular complications is an important task. Measures to minimize radiation to the posterior fossa during treatment could potentially decrease long-term risk of radiation-induced vasculopathy and stroke in brain tumor survivors. Authors’ Note This work was done at the Children’s Hospital of Pittsburgh of University of Pittsburgh Medical Center.
Author Contributions LRB and JB performed literature search and drafted the manuscript. LRB revised the manuscript and along with DC took care of the patient. GZ described the radiologic findings. DC and GZ reviewed the manuscript.
Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The authors received no financial support for the research, authorship, and/or publication of this article.
Ethical Approval Departmental policy does not require ethical approval for case reports in which the patient’s anonymity is preserved.
Downloaded from jcn.sagepub.com at MEMORIAL UNIV OF NEWFOUNDLAND on December 12, 2014
Bansal et al
3
References 1. Amlie-Lefond C, Se´bire G, Fullerton HJ. Recent developments in childhood arterial ischaemic stroke. Lancet Neurol. 2008;7:425-435. 2. Lanthier S, Carmant L, David M, Larbrisseau A, deVeber G. Stroke in children: the coexistence of multiple risk factors predicts poor outcome. Neurology. 2000;54:371-378. 3. Campen CJ, Kranick SM, Kasner SE, et al. Cranial irradiation increases risk of stroke in pediatric brain tumor survivors. Stroke. 2012;43:3035-3040. 4. Mueller S, Fullerton HJ, Stratton K, et al. Radiation, atherosclerotic risk factors, and stroke risk in survivors of pediatric cancer: a report
from the Childhood Cancer Survivor Study. Int J Radiat Oncol Biol Phys. 2013;86:649-655. 5. Mueller S, Sear K, Hills NK, et al. Risk of first and recurrent stroke in childhood cancer survivors treated with cranial and cervical radiation therapy. Int J Radiat Oncol Biol Phys.2013;86:643-648. 6. Pietila¨ S, Ma¨kipernaa A, Sieva¨nen H, et al. Obesity and metabolic changes are common in young childhood brain tumor survivors. Pediatr Blood Cancer. 2009;52:853-859. 7. Grenier Y, Tomita T, Marymont MH, Byrd S, Burrowes DM. Late postirradiation occlusive vasculopathy in childhood medulloblastoma—report of two cases. J Neurosurg. 1998;89:460-464.
Downloaded from jcn.sagepub.com at MEMORIAL UNIV OF NEWFOUNDLAND on December 12, 2014
