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Everolimus Alleviates Obstructive Hydrocephalus due to Subependymal Giant Cell Astrocytomas
Pediatric Neurology xxx (2017) 1e5
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Clinical Observations
Everolimus Alleviates Obstructive Hydrocephalus due to Subependymal Giant Cell Astrocytomas Romina Moavero MD a, b, *, Andrea Carai MD c, Angela Mastronuzzi MD d, Sara Marciano MD a, Federica Graziola MD a, Federico Vigevano MD b, Paolo Curatolo MD a a
Child Neurology and Psychiatry Unit, Systems Medicine Department, Tor Vergata University of Rome, Rome, Italy Child Neurology Unit, Department of Neuroscience and Neurorehabilitation, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy c Neurosurgery Unit, Department of Neuroscience and Neurorehabilitation, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy d Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy b
abstract BACKGROUND: Subependymal giant cell astrocytomas (SEGAs) are low-grade tumors affecting up to 20% of patients
with tuberous sclerosis complex (TSC). Early neurosurgical resection has been the only standard treatment until few years ago when a better understanding of the molecular pathogenesis of TSC led to the use of mammalian target of rapamycin (mTOR) inhibitors. Surgical resection of SEGAs is still considered as the first line treatment in individuals with symptomatic hydrocephalus and intratumoral hemorrhage. We describe four patients with symptomatic or asymptomatic hydrocephalus who were successfully treated with the mTOR inhibitor everolimus. METHODS: We collected the clinical data of four consecutive patients presenting with symptomatic or asymptomatic hydrocephalus due to a growth of subependymal giant cell atrocytomas and who could not undergo surgery for different reasons. RESULTS: All patients experienced a clinically significant response to everolimus and an early shrinkage of the SEGA with improvement in ventricular dilatation. Everolimus was well tolerated by all individuals. CONCLUSIONS: Our clinical series demonstrate a possible expanding indication for mTOR inhibition in TSC, which can be considered in patients with asymptomatic hydrocephalus or even when the symptoms already appeared. It offers a significant therapeutic alternative to individuals that once would have undergone immediate surgery. Everolimus might also allow postponement of a neurosurgical resection, making it elective with an overall lower risk. Keywords: tuberous sclerosis complex, mTOR inhibitors, SEGA, everolimus, hydrocephalus, treatment
Pediatr Neurol 2017; -: 1-5 Ó 2016 Elsevier Inc. All rights reserved. Introduction
Subependymal giant cell astrocytomas (SEGAs) are glioneuronal low-grade tumors affecting up to 20% of patients with tuberous sclerosis complex (TSC).1 They mostly occur in the first two decades of life, but they have also been described in the prenatal and neonatal periods.1 Because of their typical location near the foramen of Monro and
Article History: Received July 31, 2016; Accepted in final form November 19, 2016 * Communications should be addressed to: Dr. Moavero; Child Neurology and Psychiatry Unit; Systems Medicine Department; Tor Vergata University of Rome; 00133 Rome, Italy. E-mail address: [email protected] 0887-8994/$ e see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2016.11.003
tendency to grow, SEGAs can lead to obstruction of cerebrospinal fluid flow, thus representing a major cause of morbidity and mortality in patients affected by TSC.2,3 SEGAs are dynamic lesions; they are usually slow-growing tumors, but they can present an unexpected fast and aggressive growth.3 According to European and American recommendations, neuroimaging surveillance is required every one to three years in all subjects with TSC up to age 25 years.2,4 Growth after this age may occur rarely.5,6 Early neurosurgical resection has been the only standard treatment for SEGAs until few years ago when a better understanding of the molecular pathogenesis of TSC led to the use of mammalian target of rapamycin (mTOR) inhibitors.2 Whenever possible, surgery should not be delayed; however, this option might result risky in patients
2
R. Moavero et al. / Pediatric Neurology xxx (2017) 1e5
TABLE. Brief Summary of Clinical Details of the Four Patients Presented
Patient No.
Neurologic Involvement
Systemic Involvement
1
Sporadic focal seizures (infantile spasms onset at 6 months of life) treated with phenobarbital and carbamazepine Borderline cognitive level Behavioral problems (temper tantrum) treated with risperidone No seizures, normal cognitive level
Bilateral renal angiomyolipomas Skin lesions Ungueal fibromas Retinal hamartomas
2
3
4
Highly refractory epilepsy (onset in the first year of life) treated with phenobarbital, oxcarbazepine, clobazam, vigabatrin Severe learning disability Behavioral disturbance (aggressiveness, hyperactivity) treated with olanzapine Focal seizures (onset in the first year of life) treated with topiramate and carbamazepine Mild learning disability Behavioral disturbances (aggressiveness, temper tantrum) treated with quetiapine
with large and or bilateral lesions or in those cases with severe systemic complications.7,8 Everolimus is a selective inhibitor of the mTOR complex, which demonstrated consistent SEGA shrinkage with increasing or stable benefits after a long follow-up and an overall good safety profile.9,10 These positive results led to its approval by the Food and Drug Administration and European Medicine Agency for TSC-related SEGA not suitable for surgery. Clinicians are therefore challenged to choose between two different therapeutic options in an attempt to individualize the treatment strategy.11 Surgical resection of SEGA is still considered to be the first line treatment in individuals with symptomatic hydrocephalus and intratumoral hemorrhage.2,4 However, the institutional expertise and patients’ characteristics are the main factors determining the therapeutic choice.12
Forehead fibroma Shagreen patch Sclerotic bone lesion of vertebral bodies Bilateral renal angiomyolipomas Skin lesions Ungueal fibromas
Renal angiomyolipomas (nephrectomy þ contralateral embolization) Skin lesions Systemic hypertension
We describe four patients presenting symptomatic or asymptomatic hydrocephalus who were successfully treated with everolimus. Patient Description Clinical details of all patients are presented in Table.
Patient 1 Patient 1 (partially reported in Moavero et al.3) was referred to an emergency department at age 17 years because of intracranial hypertension. Magnetic resonance imaging (MRI) revealed acute hydrocephalus, and resective surgery was performed without complications. However, 18 months later, a new subtotal resective surgery was performed because of a second episode of obstructive hydrocephalus. Five years later the patient was randomized to the placebo arm of the EXIST-2 study (NCT00790400 clinicaltrials.gov).
FIGURE 1. Serial brain MRI of Patient 2. The first image at baseline shows a large right SEGA determining a midline shift and ventricular enlargement. The images at six and 12 months reveal a reduction in the major lesion, with normalization of ventricles size. MRI, magnetic resonance imaging; SEGA, subependymal giant cell astrocytoma. (The color version of this figure is available in the online edition.)
R. Moavero et al. / Pediatric Neurology xxx (2017) 1e5
3
FIGURE 2. Brain MRI of Patient 3 at treatment day one and after ten months of treatment. The size of SEGA appears to be significantly reduced, and the midline shifting is much less evident. Left ventricular dilatation, which can be well seen in the first examination, is no longer detectable at the last MRI follow-up. MRI, magnetic resonance imaging; SEGA, subependymal giant cell astrocytoma.
Because of a SEGA progression everolimus was then started at the dosage of 10 mg/day (approximately 5 mg/m2/day), with mean serum levels ranging from 4 to 5 ng/mL. Ten days after initiating everolimus, he complained persistent headache and asthenia because of obstructive hydrocephalus. Waiting for the effect of everolimus a temporary external drainage was placed and further resective surgery was avoided. After 12 weeks of treatment the MRI revealed a 40% reduction in total SEGA volume from baseline. The last volumetric assessment after three years of everolimus treatment revealed a total decrease of 57% in SEGA volume. No adverse events were observed during the treatment, which is still ongoing after five years.
Patient 2 Patient 2 at 21 years of age was diagnosed with a large SEGA (diameter greater than 2 cm) located near the right foramen of Monro, with an initial ventricular enlargement (Fig 1). Everolimus was started at the dosage of 5 mg/day (approximately 3 mg/m2/day), with mean serum levels of 6 ng/mL. MRI performed three weeks after the onset of everolimus already revealed a small reduction in SEGA volume. Six months later, ventricular enlargement appeared to be reduced, with an overall stabilization of the SEGA size after one year of treatment (Fig 1). The treatment is ongoing after 18 months without significant adverse events.
FIGURE 3. Brain MRI of Patient 4 at baseline and at her first neuroimaging control after about one month of treatment. A marked shrinkage in the lesion, above all in its cystic component, is evident.
4
R. Moavero et al. / Pediatric Neurology xxx (2017) 1e5
Patient 3 Patient 3 underwent complete surgical removal of a right SEGA when he was 15 years old. However, a subsequent surgery on the contralateral side was incomplete. When he was 29 years old, he presented with drowsiness, headache, and ataxia. Head computed tomography scan revealed obstructive hydrocephalus, which was treated with external drainage subsequently replaced by ventriculoperitoneal shunting. Taking into consideration the two previous surgeries and the systemic involvement, everolimus was started. Close neuroimaging follow-up was planned to evaluate whether tumor shrinkage and a reduced vascularization could make neurosurgery easier. Everolimus was titrated to 10 mg/day (approximately 5 mg/m2 body surface area [BSA]), with mean serum levels of 4 to 5 ng/mL. The patient has now taken everolimus therapy for 15 months without significant adverse events. SEGA volume decreased over time (Fig 2).
Patient 4 Patient 4, at age 27 years, presented with a significant growth of a large SEGA with a cystic component, located near the right foramen of Monro with a midline shift. Because of the size of the lesion, the presence of systemic comorbidities, and the high surgical risk, everolimus was started at the dosage of 5 mg/day (about 3 mg/m2/day). A brain MRI after four weeks of everolimus treatment revealed an impressive reduction in the SEGA, mainly in its cystic component (Fig 3).
label or compassionate therapy because of the risks associated with surgery and the presence of sever systemic comorbidities. SEGAs represent one of the major causes of mortality in TSC, and treatment with everolimus has been recently considered as a possible prevention of lifethreatening events.3 Our clinical experience demonstrates that even when symptomatic or asymptomatic hydrocephalus appears, everolimus could still be a valuable option when surgery is too risky because of the large size of lesions and lower chance of complete resection. The use of everolimus could allow elective surgery, making lesions smaller, with lower bleeding and overall surgical risks.15 In summary, our clinical series demonstrate a possible expanding indication for mTOR inhibition in TSC, which can be considered even in asymptomatic or asymptomatic hydrocephalus, being able to significantly reduce a potential life-threatening condition and thus offering a significant therapeutic alternative to individuals that once would have undergone immediate surgery. P.C. and R.M. received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 602391 (www.epistop.eu).
Discussion
Everolimus’ role in treating asymptomatic growing SEGA secondary to TSC for which there is no planned surgery is now well-established.2 However, there are few data on its use when ventricular enlargement is present and the risk of hydrocephalus is really high because of an initial obstruction of the foramen of Monro or in the presence of symptomatic hydrocephalus, because in these cases surgery is still considered the preferred therapeutic option.8 There are only anecdotal reports of patients with hydrocephalus treated with everolimus. Everolimus showed impressive efficacy in a ten-year-old boy with three prior SEGA resections who presented with deteriorating neurologic conditions.13 Two adults with TSC, with recurrent shunt malfunctions and persistent communicating hydrocephalus, have also been successfully treated with everolimus.14 An impressive response to everolimus and an early shrinkage with a significant improvement in ventricular dilatation occurred in all of our patients. Individuals with a longer follow-up experienced a progressive decrease in SEGA size, with ventricles back to a normal or near-normal size, and midline in the right position. A dosage of 2.5 mg was administered for BSA < 1.2 m2, 5 mg for BSA 1.3 to 2.1 m2, and 7.5 mg for higher BSA. Dosage was then titrated up to a maximum of 10 mg/day to reach the serum therapeutic range, considered to be 5 to 15 ng/mL.9 The presence of large and/or bilateral SEGA, history of previous neurosurgical resections, or severe systemic comorbidities make the choice of the best therapeutic option difficult. In our clinical series, two patients presented with symptoms of increased intracranial pressure, whereas in the remaining two patients neuroimaging suggested a very high risk of hydrocephalus, thus placing them in an emergency situation. A temporary or permanent shunt was necessary to acutely reduce the intracranial pressure in two patients. In all our patients, everolimus was used as an off-
References 1. Curatolo P, Moavero R, de Vries PJ. Neurological and neuropsychiatric aspects of tuberous sclerosis complex. Lancet Neurol. 2015;14: 733-745. 2. Jozwiak S, Nabbout R, Curatolo P, Participants of the TSC Consensus Meeting for SEGA and Epilepsy Management. Management of subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC): clinical recommendations. Eur J Paediatr Neurol. 2013;17:348-352. 3. Moavero R, Romagnoli G, Graziola F, Curatolo P. Mammalian target of rapamycin inhibitors and life-threatening conditions in tuberous sclerosis complex. Semin Pediatr Neurol. 2015;22:282-294. 4. Krueger DA, Northrup H, International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013;49:255-265. 5. Adriaensen ME, Schaefer-Prokop CM, Stijnen T, Duyndam DA, Zonnenberg BA, Prokop M. Prevalence of subependymal giant cell tumors in patients with tuberous sclerosis and a review of the literature. Eur J Neurol. 2009;16:691-696. 6. Northrup H, Krueger DA, International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013;49: 243-254. 7. Sun P, Kohrman M, Liu J, Guo A, Rogerio J, Krueger D. Outcomes of resecting subependymal giant cell astrocytoma (SEGA) among patients with SEGA-related tuberous sclerosis complex: a national claims database analysis. Curr Med Res Opin. 2012;28:657-663. 8. Curatolo P, Bjornvold M, Dill PE, et al. The role of mTOR inhibitors in the treatment of patients with tuberous sclerosis complex: evidence-based and expert opinions. Drugs. 2016;76:551-565. 9. Franz DN, Belousova E, Sparagana S, et al. Everolimus for subependymal giant cell astrocytoma in patients with tuberous sclerosis complex: 2-year open-label extension of the randomised EXIST-1 study. Lancet Oncol. 2014;15:1513-1520. 10. Franz DN, Belousova E, Sparagana S, et al. Long-term use of everolimus in patients with tuberous sclerosis complex: final results from the EXIST-1 Study. PLoS One. 2016;11:e0158476. 11. Curatolo P, Moavero R. mTOR inhibitors in tuberous sclerosis complex. Curr Neuropharmacol. 2012;10:404-415. 12. Roth J, Roach ES, Bartels U, et al. Subependymal giant cell astrocytoma: diagnosis, screening, and treatment. Recommendations from
R. Moavero et al. / Pediatric Neurology xxx (2017) 1e5 the International Tuberous Sclerosis Complex Consensus Conference 2012. Pediatr Neurol. 2013;49:439-444. 13. Perek-Polnik M, Jozwiak S, Jurkiewicz E, Perek D, Kotulska K. Effective everolimus treatment of inoperable, life-threatening subependymal giant cell astrocytoma and intractable epilepsy in a patient with tuberous sclerosis complex. Eur J Paediatr Neurol. 2012;16:83-85.
5
14. Laviv Y, Jackson S, Rappaport ZH. Persistent communicating hydrocephalus in adult tuberous sclerosis patients: a possible therapeutic role for everolimus. Acta Neurochir (Wien). 2015;157:241-245. 15. Berhouma M. Management of subependymal giant cell tumors in tuberous sclerosis complex: the neurosurgeon’s perspective. World J Pediatr. 2010;6:103-110.
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Clinical Observations
Everolimus Alleviates Obstructive Hydrocephalus due to Subependymal Giant Cell Astrocytomas Romina Moavero MD a, b, *, Andrea Carai MD c, Angela Mastronuzzi MD d, Sara Marciano MD a, Federica Graziola MD a, Federico Vigevano MD b, Paolo Curatolo MD a a
Child Neurology and Psychiatry Unit, Systems Medicine Department, Tor Vergata University of Rome, Rome, Italy Child Neurology Unit, Department of Neuroscience and Neurorehabilitation, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy c Neurosurgery Unit, Department of Neuroscience and Neurorehabilitation, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy d Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy b
abstract BACKGROUND: Subependymal giant cell astrocytomas (SEGAs) are low-grade tumors affecting up to 20% of patients
with tuberous sclerosis complex (TSC). Early neurosurgical resection has been the only standard treatment until few years ago when a better understanding of the molecular pathogenesis of TSC led to the use of mammalian target of rapamycin (mTOR) inhibitors. Surgical resection of SEGAs is still considered as the first line treatment in individuals with symptomatic hydrocephalus and intratumoral hemorrhage. We describe four patients with symptomatic or asymptomatic hydrocephalus who were successfully treated with the mTOR inhibitor everolimus. METHODS: We collected the clinical data of four consecutive patients presenting with symptomatic or asymptomatic hydrocephalus due to a growth of subependymal giant cell atrocytomas and who could not undergo surgery for different reasons. RESULTS: All patients experienced a clinically significant response to everolimus and an early shrinkage of the SEGA with improvement in ventricular dilatation. Everolimus was well tolerated by all individuals. CONCLUSIONS: Our clinical series demonstrate a possible expanding indication for mTOR inhibition in TSC, which can be considered in patients with asymptomatic hydrocephalus or even when the symptoms already appeared. It offers a significant therapeutic alternative to individuals that once would have undergone immediate surgery. Everolimus might also allow postponement of a neurosurgical resection, making it elective with an overall lower risk. Keywords: tuberous sclerosis complex, mTOR inhibitors, SEGA, everolimus, hydrocephalus, treatment
Pediatr Neurol 2017; -: 1-5 Ó 2016 Elsevier Inc. All rights reserved. Introduction
Subependymal giant cell astrocytomas (SEGAs) are glioneuronal low-grade tumors affecting up to 20% of patients with tuberous sclerosis complex (TSC).1 They mostly occur in the first two decades of life, but they have also been described in the prenatal and neonatal periods.1 Because of their typical location near the foramen of Monro and
Article History: Received July 31, 2016; Accepted in final form November 19, 2016 * Communications should be addressed to: Dr. Moavero; Child Neurology and Psychiatry Unit; Systems Medicine Department; Tor Vergata University of Rome; 00133 Rome, Italy. E-mail address: [email protected] 0887-8994/$ e see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2016.11.003
tendency to grow, SEGAs can lead to obstruction of cerebrospinal fluid flow, thus representing a major cause of morbidity and mortality in patients affected by TSC.2,3 SEGAs are dynamic lesions; they are usually slow-growing tumors, but they can present an unexpected fast and aggressive growth.3 According to European and American recommendations, neuroimaging surveillance is required every one to three years in all subjects with TSC up to age 25 years.2,4 Growth after this age may occur rarely.5,6 Early neurosurgical resection has been the only standard treatment for SEGAs until few years ago when a better understanding of the molecular pathogenesis of TSC led to the use of mammalian target of rapamycin (mTOR) inhibitors.2 Whenever possible, surgery should not be delayed; however, this option might result risky in patients
2
R. Moavero et al. / Pediatric Neurology xxx (2017) 1e5
TABLE. Brief Summary of Clinical Details of the Four Patients Presented
Patient No.
Neurologic Involvement
Systemic Involvement
1
Sporadic focal seizures (infantile spasms onset at 6 months of life) treated with phenobarbital and carbamazepine Borderline cognitive level Behavioral problems (temper tantrum) treated with risperidone No seizures, normal cognitive level
Bilateral renal angiomyolipomas Skin lesions Ungueal fibromas Retinal hamartomas
2
3
4
Highly refractory epilepsy (onset in the first year of life) treated with phenobarbital, oxcarbazepine, clobazam, vigabatrin Severe learning disability Behavioral disturbance (aggressiveness, hyperactivity) treated with olanzapine Focal seizures (onset in the first year of life) treated with topiramate and carbamazepine Mild learning disability Behavioral disturbances (aggressiveness, temper tantrum) treated with quetiapine
with large and or bilateral lesions or in those cases with severe systemic complications.7,8 Everolimus is a selective inhibitor of the mTOR complex, which demonstrated consistent SEGA shrinkage with increasing or stable benefits after a long follow-up and an overall good safety profile.9,10 These positive results led to its approval by the Food and Drug Administration and European Medicine Agency for TSC-related SEGA not suitable for surgery. Clinicians are therefore challenged to choose between two different therapeutic options in an attempt to individualize the treatment strategy.11 Surgical resection of SEGA is still considered to be the first line treatment in individuals with symptomatic hydrocephalus and intratumoral hemorrhage.2,4 However, the institutional expertise and patients’ characteristics are the main factors determining the therapeutic choice.12
Forehead fibroma Shagreen patch Sclerotic bone lesion of vertebral bodies Bilateral renal angiomyolipomas Skin lesions Ungueal fibromas
Renal angiomyolipomas (nephrectomy þ contralateral embolization) Skin lesions Systemic hypertension
We describe four patients presenting symptomatic or asymptomatic hydrocephalus who were successfully treated with everolimus. Patient Description Clinical details of all patients are presented in Table.
Patient 1 Patient 1 (partially reported in Moavero et al.3) was referred to an emergency department at age 17 years because of intracranial hypertension. Magnetic resonance imaging (MRI) revealed acute hydrocephalus, and resective surgery was performed without complications. However, 18 months later, a new subtotal resective surgery was performed because of a second episode of obstructive hydrocephalus. Five years later the patient was randomized to the placebo arm of the EXIST-2 study (NCT00790400 clinicaltrials.gov).
FIGURE 1. Serial brain MRI of Patient 2. The first image at baseline shows a large right SEGA determining a midline shift and ventricular enlargement. The images at six and 12 months reveal a reduction in the major lesion, with normalization of ventricles size. MRI, magnetic resonance imaging; SEGA, subependymal giant cell astrocytoma. (The color version of this figure is available in the online edition.)
R. Moavero et al. / Pediatric Neurology xxx (2017) 1e5
3
FIGURE 2. Brain MRI of Patient 3 at treatment day one and after ten months of treatment. The size of SEGA appears to be significantly reduced, and the midline shifting is much less evident. Left ventricular dilatation, which can be well seen in the first examination, is no longer detectable at the last MRI follow-up. MRI, magnetic resonance imaging; SEGA, subependymal giant cell astrocytoma.
Because of a SEGA progression everolimus was then started at the dosage of 10 mg/day (approximately 5 mg/m2/day), with mean serum levels ranging from 4 to 5 ng/mL. Ten days after initiating everolimus, he complained persistent headache and asthenia because of obstructive hydrocephalus. Waiting for the effect of everolimus a temporary external drainage was placed and further resective surgery was avoided. After 12 weeks of treatment the MRI revealed a 40% reduction in total SEGA volume from baseline. The last volumetric assessment after three years of everolimus treatment revealed a total decrease of 57% in SEGA volume. No adverse events were observed during the treatment, which is still ongoing after five years.
Patient 2 Patient 2 at 21 years of age was diagnosed with a large SEGA (diameter greater than 2 cm) located near the right foramen of Monro, with an initial ventricular enlargement (Fig 1). Everolimus was started at the dosage of 5 mg/day (approximately 3 mg/m2/day), with mean serum levels of 6 ng/mL. MRI performed three weeks after the onset of everolimus already revealed a small reduction in SEGA volume. Six months later, ventricular enlargement appeared to be reduced, with an overall stabilization of the SEGA size after one year of treatment (Fig 1). The treatment is ongoing after 18 months without significant adverse events.
FIGURE 3. Brain MRI of Patient 4 at baseline and at her first neuroimaging control after about one month of treatment. A marked shrinkage in the lesion, above all in its cystic component, is evident.
4
R. Moavero et al. / Pediatric Neurology xxx (2017) 1e5
Patient 3 Patient 3 underwent complete surgical removal of a right SEGA when he was 15 years old. However, a subsequent surgery on the contralateral side was incomplete. When he was 29 years old, he presented with drowsiness, headache, and ataxia. Head computed tomography scan revealed obstructive hydrocephalus, which was treated with external drainage subsequently replaced by ventriculoperitoneal shunting. Taking into consideration the two previous surgeries and the systemic involvement, everolimus was started. Close neuroimaging follow-up was planned to evaluate whether tumor shrinkage and a reduced vascularization could make neurosurgery easier. Everolimus was titrated to 10 mg/day (approximately 5 mg/m2 body surface area [BSA]), with mean serum levels of 4 to 5 ng/mL. The patient has now taken everolimus therapy for 15 months without significant adverse events. SEGA volume decreased over time (Fig 2).
Patient 4 Patient 4, at age 27 years, presented with a significant growth of a large SEGA with a cystic component, located near the right foramen of Monro with a midline shift. Because of the size of the lesion, the presence of systemic comorbidities, and the high surgical risk, everolimus was started at the dosage of 5 mg/day (about 3 mg/m2/day). A brain MRI after four weeks of everolimus treatment revealed an impressive reduction in the SEGA, mainly in its cystic component (Fig 3).
label or compassionate therapy because of the risks associated with surgery and the presence of sever systemic comorbidities. SEGAs represent one of the major causes of mortality in TSC, and treatment with everolimus has been recently considered as a possible prevention of lifethreatening events.3 Our clinical experience demonstrates that even when symptomatic or asymptomatic hydrocephalus appears, everolimus could still be a valuable option when surgery is too risky because of the large size of lesions and lower chance of complete resection. The use of everolimus could allow elective surgery, making lesions smaller, with lower bleeding and overall surgical risks.15 In summary, our clinical series demonstrate a possible expanding indication for mTOR inhibition in TSC, which can be considered even in asymptomatic or asymptomatic hydrocephalus, being able to significantly reduce a potential life-threatening condition and thus offering a significant therapeutic alternative to individuals that once would have undergone immediate surgery. P.C. and R.M. received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 602391 (www.epistop.eu).
Discussion
Everolimus’ role in treating asymptomatic growing SEGA secondary to TSC for which there is no planned surgery is now well-established.2 However, there are few data on its use when ventricular enlargement is present and the risk of hydrocephalus is really high because of an initial obstruction of the foramen of Monro or in the presence of symptomatic hydrocephalus, because in these cases surgery is still considered the preferred therapeutic option.8 There are only anecdotal reports of patients with hydrocephalus treated with everolimus. Everolimus showed impressive efficacy in a ten-year-old boy with three prior SEGA resections who presented with deteriorating neurologic conditions.13 Two adults with TSC, with recurrent shunt malfunctions and persistent communicating hydrocephalus, have also been successfully treated with everolimus.14 An impressive response to everolimus and an early shrinkage with a significant improvement in ventricular dilatation occurred in all of our patients. Individuals with a longer follow-up experienced a progressive decrease in SEGA size, with ventricles back to a normal or near-normal size, and midline in the right position. A dosage of 2.5 mg was administered for BSA < 1.2 m2, 5 mg for BSA 1.3 to 2.1 m2, and 7.5 mg for higher BSA. Dosage was then titrated up to a maximum of 10 mg/day to reach the serum therapeutic range, considered to be 5 to 15 ng/mL.9 The presence of large and/or bilateral SEGA, history of previous neurosurgical resections, or severe systemic comorbidities make the choice of the best therapeutic option difficult. In our clinical series, two patients presented with symptoms of increased intracranial pressure, whereas in the remaining two patients neuroimaging suggested a very high risk of hydrocephalus, thus placing them in an emergency situation. A temporary or permanent shunt was necessary to acutely reduce the intracranial pressure in two patients. In all our patients, everolimus was used as an off-
References 1. Curatolo P, Moavero R, de Vries PJ. Neurological and neuropsychiatric aspects of tuberous sclerosis complex. Lancet Neurol. 2015;14: 733-745. 2. Jozwiak S, Nabbout R, Curatolo P, Participants of the TSC Consensus Meeting for SEGA and Epilepsy Management. Management of subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC): clinical recommendations. Eur J Paediatr Neurol. 2013;17:348-352. 3. Moavero R, Romagnoli G, Graziola F, Curatolo P. Mammalian target of rapamycin inhibitors and life-threatening conditions in tuberous sclerosis complex. Semin Pediatr Neurol. 2015;22:282-294. 4. Krueger DA, Northrup H, International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013;49:255-265. 5. Adriaensen ME, Schaefer-Prokop CM, Stijnen T, Duyndam DA, Zonnenberg BA, Prokop M. Prevalence of subependymal giant cell tumors in patients with tuberous sclerosis and a review of the literature. Eur J Neurol. 2009;16:691-696. 6. Northrup H, Krueger DA, International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013;49: 243-254. 7. Sun P, Kohrman M, Liu J, Guo A, Rogerio J, Krueger D. Outcomes of resecting subependymal giant cell astrocytoma (SEGA) among patients with SEGA-related tuberous sclerosis complex: a national claims database analysis. Curr Med Res Opin. 2012;28:657-663. 8. Curatolo P, Bjornvold M, Dill PE, et al. The role of mTOR inhibitors in the treatment of patients with tuberous sclerosis complex: evidence-based and expert opinions. Drugs. 2016;76:551-565. 9. Franz DN, Belousova E, Sparagana S, et al. Everolimus for subependymal giant cell astrocytoma in patients with tuberous sclerosis complex: 2-year open-label extension of the randomised EXIST-1 study. Lancet Oncol. 2014;15:1513-1520. 10. Franz DN, Belousova E, Sparagana S, et al. Long-term use of everolimus in patients with tuberous sclerosis complex: final results from the EXIST-1 Study. PLoS One. 2016;11:e0158476. 11. Curatolo P, Moavero R. mTOR inhibitors in tuberous sclerosis complex. Curr Neuropharmacol. 2012;10:404-415. 12. Roth J, Roach ES, Bartels U, et al. Subependymal giant cell astrocytoma: diagnosis, screening, and treatment. Recommendations from
R. Moavero et al. / Pediatric Neurology xxx (2017) 1e5 the International Tuberous Sclerosis Complex Consensus Conference 2012. Pediatr Neurol. 2013;49:439-444. 13. Perek-Polnik M, Jozwiak S, Jurkiewicz E, Perek D, Kotulska K. Effective everolimus treatment of inoperable, life-threatening subependymal giant cell astrocytoma and intractable epilepsy in a patient with tuberous sclerosis complex. Eur J Paediatr Neurol. 2012;16:83-85.
5
14. Laviv Y, Jackson S, Rappaport ZH. Persistent communicating hydrocephalus in adult tuberous sclerosis patients: a possible therapeutic role for everolimus. Acta Neurochir (Wien). 2015;157:241-245. 15. Berhouma M. Management of subependymal giant cell tumors in tuberous sclerosis complex: the neurosurgeon’s perspective. World J Pediatr. 2010;6:103-110.