- •Pediatric brain tumors are the most common cause of death in pediatric cancer.
- •Seizures are one of the most common symptoms in pediatric brain tumors.
- •Supratentorial brain tumors that involve gray matter are more epileptogenic.
- •Dysembryoplastic neuroepithelial tumor and ganglioglioma are particularly epileptogenic.
- •Newer drugs with less interactions are preferred for seizures caused by tumors.
3. Characteristics of seizures in children with brain tumors
4. Classification of brain tumors in children with approximate frequency
|Supratentorial brain tumors|
|Diffuse astrocytoma (grade II)||++||Cerebral hemispheres: frontal and temporal lobes (less frequently, brainstem and spinal cord)||Meningeal fibrils. No mitoses. No vascular proliferation||+++|
|Anaplastic astrocytoma (grade III)||+||Supratentorial||Increased cellularity, pleomorphism, mitoses||−|
|Glioblastoma multiforme (grade IV)||+||Supratentorial||Increased cellularity, pleomorphism, mitoses. Vascular proliferation. Necrosis||−−|
|Ganglioglioma||+||Cerebral hemispheres: temporal > frontal||Mixture of neoplastic glial and neuronal elements||++++|
|Dysembryoplastic neuroepithelial tumor (DNET)||−||Cerebral hemispheres: temporal > frontal > parietal lobes. Centered in the cerebral cortex, although it might extend to the white matter||Multinodular microcystic lesions with floating neurons. Pleomorphism, glial-neural elements. May be surrounded by areas of dysplasia. Limited mitoses.||++++|
|Supratentorial primitive neuroectodermal tumor||+||Cerebral hemispheres||Undifferentiated or poorly differentiated neuroepithelial cells. Pathology similar to neuroblastoma.||+|
|Variable depending on pathology and age. Higher risk of relapse than medulloblastoma|
|Oligodendroglioma||−||Cerebral hemispheres (rarely medulla)||Honeycomb appearance: repetitive pattern of similar rounded cells with perinuclear halo||Variable depending on the other histologic components of the tumor|
|Posterior fossa tumors|
|Pilocytic astrocytoma||++++||Cerebellum (less frequently cerebral hemispheres, optic pathway, hypothalamus, and brain stem)||Compact areas with Rosenthal fibers and spongy areas with microcysts||++++|
|Medulloblastoma||++++||Posterior fossa||Classic variant: densely packed cells with hyperchromatic nuclei and scant cytoplasm||+++|
|Desmoplastic/nodular variant: nodular, reticular-free zones of neuronal maturation surrounded by densely-packed mitotically active cells||Variable depending on pathology and age|
|Extensive nodularity variant: expanded lobular architecture|
|Large cell variant: monomorphic cells with large, round, vesicular nuclei with prominent nucleoli|
|Anaplastic variant: cells with marked nuclear pleomorphism and nuclear moulding|
|Ependymoma||+++||2/3 infratentorial, 1/3 supratentorial||Rosettes and pseudorosettes. Histologic features predict degree of malignancy poorly||++|
|Hypothalamic hamartoma||−||Hypothalamus||Abnormally distributed, but cytologically normal small neurons and glia||++++|
4.1 Supratentorial tumors
- a)Astrocytomas represent approximately one third of all intracranial tumors and the most common histology in the supratentorial region [1,3]. The World Health Organization classification grades tumors according to an increasing level of malignancy so that grade I is benign, grade II is low grade, grade III is anaplastic or moderately malignant, and grade IV is highly malignant []. Fortunately, most pediatric astrocytomas are low grade. The most common pediatric astrocytoma is pilocytic astrocytoma (grade I) which occurs most frequently in the cerebellum, hence we will discuss it under the infratentorial tumors. Grade II diffuse astrocytomas represent approximately 15% of pediatric astrocytomas and have a biphasic distribution with peaks at 2–4 years of age and in adolescence []. They appear most commonly in the frontal and temporal lobes as heterogeneous masses []. Pathologically, they consist of a fibrillary pattern that infiltrates neighboring brain structures []. Their 5-year survival rate varies between 50–100% depending on the extent of surgical resection []. Anaplastic astrocytoma (grade III) and glioblastoma multiforme (grade IV) peak at 9–10 years of age and appear most frequently as supratentorial masses with cystic components and necrosis being more frequent with increasing malignancy []. Pathologically, they consist of increased cellularity, pleomorphism, and in grade IV, vascular proliferation and areas of necrosis []. Their 5-year survival rates are approximately 15–30% [].
- b)Gangliogliomas (Fig. 1) represent approximately 3% of brain tumors and 6% of supratentorial pediatric brain tumors []. They peak in adolescence and the most common presenting sign is seizures []. They appear most frequently in the temporo-parieto-occipital regions followed by the frontal lobes and the posterior fossa [19,20,21]. They appear as an enhancing mass with partially cystic appearance in at least 40% of the cases []. Calcification can be found in 40–50% of cases []. Pathologically, they consist of a mixture of neoplastic glial and neuronal elements: clusters of large ganglion-like neurons mixed with neoplastic astrocytes [19,21]. Most pediatric gangliogliomas are benign (World Health Organization grade I) [19,21]. The 5-year survival approaches 100%, but depending on the extent of the resection tumors may recur within 5-years of resection [].
- c)Dysembrioplastic neuroepitelial tumors (DNETs) (Fig. 2) are rare, represent approximately 1% of pediatric brain tumors, and appear most frequently in older children [18,23]. They appear as a well-circumscribed cystic mass most commonly centered in the cerebral cortex, particularly frequent in the temporal lobe [18,24]. Pathologically, they consist of columns of axon and oligodendroglial bundles that surround neurons floating in an eosinophilic matrix; DNETs are slow-growing and they are frequently associated with cortical dysplasias []. The 5-year survival approaches 100%, although they can recur after surgical resection [].
- d)Oligodendrogliomas are rare representing 1–2% of pediatric brain tumors [3,25]. They appear as a mass with nodular calcifications in the cerebral hemispheres []. Pathologically, they consist of a honeycomb structure with a monotonous collection of uniform rounded cells with clear cytoplasm. Oligodendrogliomas usually appear as a mixed glioma with different histologic components, so that the 5-year survival is variable depending on the other components of the tumor.
- e)Supratentorial primitive neuroectodermal tumors represent approximately 5% of all pediatric supratentorial tumors []. They peak in the first 5 years of life, sometimes as a congenital tumor []. They appear in the cerebral hemispheres as large, heterogeneous masses, often with necrosis, cystic degeneration, calcification, and osseous erosion []. Their histology is similar but the prognosis is worse to that of the most frequent infratentorial primitive neuroectodermal tumor: the medulloblastoma [].
4.2 Infratentorial tumors
- a)Astrocytomas. Pilocytic astrocytomas represent approximately 20% of all pediatric astrocytomas and peak at 5–14 years of age [18,23]. They appear most commonly in the cerebellum [18,26] as a well-defined mass or, more commonly, as a single large cyst with a mural node []. Pathologically, they consist of an alternation of compact areas with Rosenthal fibers and spongy areas with microcysts; calcification occurs in approximately one fifth of cases []. They can remain stable during prolonged periods and their 5-year survival exceeds 90% [18,26].
- b)Medulloblastomas represent 10–15% of all pediatric brain tumors [1,3,23] and peak at 5–9 years of age []. In contrast with most other pediatric brain tumors where there is no gender differences, there is more than twofold preference for males []. They appear as a large gadolinium-enhanced mass in the fourth ventricle, frequently obstructing the cerebrospinal fluid flow and causing hydrocephalus []. Pathologically, they consist of densely packed cells with round to oval or carrot-shaped hyperchromatic nuclei surrounded by scant cytoplasm []. Five-year survival rates in medulloblastoma have drastically improved in the last years and now are 50–70% depending on pathology and age [
Childhood medulloblastoma.Crit Rev Oncol Hematol. 2016; 105 (Review. PMID: 27375228): 35-51https://doi.org/10.1016/j.critrevonc.2016.05.012
- Massimino M.
- Biassoni V.
- Gandola L.
- Garrè M.L.
- Gatta G.
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- et al.
- c)Ependymomas represent 2–14% of pediatric brain tumors [1,3,23] with a peak at 0–5 years of age []. Approximately two thirds of ependymomas are infratentorial while one third is supratentorial: infratentorial location is more common in patients younger than 3 years of age and supratentorial location is more common in patients older than 3 years of age []. They appear as heterogeneous masses with frequent hemorrhage and necrosis []. Pathologically, they show ependymal rosettes with tumor cells lining a small central lumen []. 5-year survival is 20–80% and highly dependent on extent of surgical resection, age, and location [].
- d)Hypothalamic hamartomas are rare affecting approximately 1/200,000 children and adolescents []. They are congenital, non-progressive masses that arise from the ventral hypothalamus and tuber cinereum []. They appear as non-enhancing suprasellar masses of gray matter intensity []. Pathologically, they consist of abnormally distributed, but cytologically normal small neurons and glia []. Five-year survival approaches 100% [].
5. Clinical presentation of the pediatric brain tumors most associated with seizures
MacDonald T, Packer R. Pediatric astrocytoma clinical presentation. Medscape. http://emedicine.medscape.com/article/985927-clinical [accessed 23.11.16].
5.2 Ganglioglioma (Fig. 1)
5.3 Dysembryoplastic neuroepithelial tumor (DNET) (Fig. 2)
- Wu C.T.
- Tsay P.K.
- Jaing T.H.
- Chen S.H.
- Tseng C.K.
- Jung S.M.
5.5 Hypothalamic harmartoma
5.6 Seizures in infratententorial tumors
6. Seizures secondary to brain metastases, leukemias, and treatment with chemotherapy and radiotherapy
7. Pathophysiological mechanisms by which brain tumors cause seizures
8. Treatment of seizures caused by pediatric brain tumors
- Spena G.
- Schucht P.
- Seidel K.
- Rutten G.J.
- Freyschlag C.F.
- D’Agata F.
- et al.
Drappatz J, Wen P, Avila E. Seizures in patients with primary and metastatic brain tumors. Uptodate. http://www.uptodate.com/contents/seizures-in-patients-with-primary-and-metastatic-brain-tumors [accessed 23.11.16].
|Effect of antiepileptic drugs on chemotherapeutic agents|
|Main AEDs that cause lower levels of chemotherapeutic agents||Phenobarbital, phenytoin, carbamazepine|
|Main AEDs that cause increased levels of chemotherapeutic agents||Valproate|
|Effect of chemotherapeutic agents on antiepileptic drugs|
|Main chemotherapeutic agents that lower levels of phenytoin||Nitrosureas, cisplatin, etoposide, carmustine, dacarbazine, carboplatin, vinblastine, methotrexate, bleomycin, dexamethasone|
|Main chemotherapeutic agents that lower levels of carbamazepine||Cisplatin, adriamycine|
|Main chemotherapeutic agents that lower levels of valproate||Methotrexate, cisplatin, adriamycine|
|Main chemotherapeutic agents that increase levels of phenytoin||Dexamethasone, 5-fluorouracil, tegafur, tamoxifen|
Conflict of interest statement
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