Neurologic Manifestations of Ependymoma

Ependymomas are neoplasms of ependymal cells that occur throughout the entire neuraxis in association with the lining of the cerebral ventricles and central canal of the spinal cord.

Ependymomas occur most commonly in the intracranial and intraspinal areas, with lesions rarely occurring in the sacral area. Other unusual ectopic sites of ependymoma are the mediastinum, ovary, and broad ligament. In general, the anatomic location determines the pathophysiological manifestations of the tumor. Supratentorial tumors present with mass effect, focal neurological signs, and occasional obstruction of ventricular outflow. The relationship with the ventricular system is more apparent in tumors of the posterior fossa (mostly of the fourth ventricle), which usually present with obstructive hydrocephalus with or without signs of brain stem compression. See the images below.

CT scan without contrast, axial view, demonstrates mixed but predominantly hyperdense tumor in the posterior fossa with severe obstructive hydrocephalus.

CT scan with contrast, axial view shows moderately intense contrast enhancement (compare with the previous image).

Frequency

United States

Ependymomas are infrequent tumors, representing 2-8% of all brain tumors. However, ependymomas are the third most common brain tumor in children (8-12%) with up to 30% occurring in children younger than 3 years. Half of the ependymomas occur in the first 2 decades of life; two-thirds are located in the posterior fossa (>90% are in the fourth ventricle). Interestingly, despite their overall low frequency, ependymomas are the most frequent neuroepithelial tumors of the spinal cord.

Mortality/Morbidity

From the biological perspective, ependymomas do not usually proliferate rapidly, are not invasive, and usually do not metastasize.[1] The associated morbidity can mainly be accounted for by the local space-occupying effects of the tumor. However, children and adolescents, the oldest adult age group, cases diagnosed with anaplastic ependymoma, and/or tumor location in a brainstem site had lowest survival rates.[1] In unusual cases, the risk of sudden death from large intracranial ependymomas results from increased intracranial pressure secondary to obstructive hydrocephalus.

Race

No race predilection is reported.

Sex

No sex predilection is reported.

Age

Peak age at presentation ranges from 7 weeks to 16 years with a mean of 3.7 years. A second, lower peak age of presentation occurs in the third decade of life.

Presenting features are insidious and progressive in nature.

• Nausea and vomiting (80%) is the most common presenting symptom, secondary to increased intracranial pressure.

• Headache (60%), due to the local effect of pressure or increased intracranial pressure, is usually worse in the morning.

• Change in behavior (50%) includes lethargy, irritability, diminished social interaction, and loss of appetite (prevalent in younger children).

• Difficulty with balance (30%) reflects cerebellar involvement or mass effect.

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• Papilledema (60%)

• Ataxia (45%)

• Nystagmus with or without gaze palsy (40%)

• Lower cranial nerve palsies (10%)

• Apraxia or hemiparesis (20%)

• Increase in head circumference in children younger than 2 years (10%)

No particular genetic or molecular marker or familial predisposition has been identified for this tumor type. In one series, only a few ependymomas were reported to be hyperdiploid or tetraploid.

• Other diagnostic considerations:

  • Meningitis

  • Encephalitis

  • Other brain tumors (astrocytoma, medulloblastoma, oligodendroglioma)

  • Meningitis and encephalitis can be readily differentiated by their more abrupt onset, associated fever, or signs of meningeal irritation.

  • Differentiation from other types of brain tumors (astrocytoma, medulloblastoma, oligodendroglioma) is radiological and pathological.

Laboratory studies are not helpful for diagnosis.

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• MRI is the diagnostic tool of choice.[2] It reveals discrete, heterogeneous masses with variable enhancement (see the images below).

  MRI, T2-weighted image, axial view, showing mixed (isodensity and hyperdensity) heterogenous nature of the tumor with some peritumoral edema.

  MRI, T1-weighted image, without contrast, sagittal view, showing the posterior fossa location, mixed (hypodensity and isodensity) signal intensity and tending to grow out of the fourth ventricle.

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  • Evidence of calcification, necrosis, and cystic change are occasionally seen; hemorrhage is rare.

  • The tumor characteristically displaces rather than infiltrates brain parenchyma with minimal peritumoral edema.

• CT scan is used in emergency situations, although its resolution is inferior to that of MRI. The CT appearance of ependymoma varies, but calcification is more evident on CT scan.

  CT scan without contrast, axial view, demonstrates mixed but predominantly hyperdense tumor in the posterior fossa with severe obstructive hydrocephalus.

  CT scan with contrast, axial view shows moderately intense contrast enhancement (compare with the previous image).

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• Ventriculostomy is not required preoperatively because patients are usually stable. In fact, it should be avoided if possible because of the potentially fatal risk of upward herniation or hemorrhage within the tumor with brain stem compression.

• Lumbar puncture is also contraindicated because of a similar risk of downward (tonsillar) herniation preoperatively.

The presence of a classic, well-circumscribed lesion with moderate cellularity, punctuated by areas of an acellular, fibrillary zone (perivascular pseudorosettes) is common. Variants include the following:

• Clear cell type with perinuclear halo

• Papillary type with an extensive epithelial component

• True rosette formation

• Myxopapillary type with prominent perivascular and intercellular mucin[3, 4]

• Rare melanotic type containing lipofuscin and no melanin pigment

Current World Health Organization (WHO) classification grades tumors as follows:

• Subependymoma and myxopapillary tumors - Grade 1

• Ependymoma - Grade 2

• Anaplastic ependymoma - Grade 3

Only 10% of ependymomas metastasize to other areas of the neuraxis; these metastases are almost always associated with tumor recurrence at the primary site, which emphasizes the importance of local control.

A multimodality approach that encompasses maximal surgical resection in combination with adjuvant therapy is critical for achieving optimal disease control.[5] Preoperative and perioperative steroids are recommended to help limit edema and alleviate some symptoms.

Surgery remains the most effective therapy for this tumor. It establishes tissue diagnosis, restores normal cerebrospinal fluid flow, and can be used to attempt total removal of the tumor.

A second-look surgery for unexpected residual lesions that are seen on postoperative imaging in an operable location is encouraged in patients with noninvasive, benign histology.

Permanent cerebrospinal fluid (CSF) diversion with ventriculoperitoneal shunt is rarely required.

Postoperative radiation therapy substantially improves survival. Although not proven, some dose-to-response relationship probably exists.

Newer methods that target only the local tumor bed, such as high fractionation radiotherapy or stereotactic radiosurgery, may permit potential dose reduction as compared with conventional radiotherapy. It provides effective tumor control, which may help limit complications such as cognitive dysfunction, growth delay, and hypothyroidism.

Craniospinal axis radiation is recommended only for patients with radiological or pathological evidence of spinal seeding.

Overall, results of chemotherapy are disappointing.[6] Multidrug combinations using VP-16 etoposide, vincristine, CCNU (lomustine), and cisplatin offer limited benefit in patients with recurrent disease.

Gross total resection (GTR) is associated with the lowest rates of mortality, the best overall survival, and the longest progression-free survival rates.[7] Patients with WHO grade II tumors had better overall survival after GTR plus external-beam radiation therapy (EBRT) and better progression-free survival rates than after GTR alone. Patients with WHO grade III tumors had better overall survival after subtotal resection plus EBRT.[8]

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• Neurosurgeon

• Neurologist

• Radiation oncologist

• Medical oncologist

No specific medications exist for treating ependymoma.

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• Radiation therapy

• Chemotherapy

• Serial neuroimaging (MRI)

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• Admit the patient for repeat surgery.

• Admit the patient for treatment of complications from surgery, radiotherapy, or chemotherapy.

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• Hydrocephalus

• Paralysis

• Cranial nerve palsy

• Meningitis

• Bone marrow suppression

• Cognitive dysfunction

• Growth and developmental delay

• Hypothyroidism

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• Gross total resection is the most important determinant of outcome, with progression-free survival rates of 70-80% after 5 years, compared to 35% for incomplete resection.[9]

• Postoperative radiation therapy improves survival, whereas results of chemotherapy are disappointing.[6]

• Age also strongly correlates with outcome. Usually, the younger the patient, the worse the prognosis.

• In addition to age, supratentorial tumor location is associated with a worse prognosis in adult ependymoma patients. Supratentorial location was also correlated with shorter progression-free survival than infratentorial location in a multicenter retrospective analysis.[10]

• Studies in which the current WHO classification criteria were applied reported the relationship between histological grade and outcome. Biomolecular studies have identified that gain of 1q25 and epidermal growth factor receptor (EGFR) overexpression correlate to poor prognosis, whereas low expression of nucleolin correlated with a favorable outcome.[11]

Refer the patient for psychosocial counseling.