Five-Year-Old Boy With Behavioral Changes and Papilledema

A 5-year-old boy had initial symptoms of behavioral changes, nausea, vomiting, headache, weight loss, and progressive vision failure. Brain MRI revealed abnormal signal intensity in both optic nerves, the optic chiasm, the right medial temporal lobe, and tissues surrounding the right supraclinoid internal carotid artery with associated leptomeningeal and spinal cord enhancement. After nondiagnostic dural and spinal arachnoid biopsies, a temporal lobe biopsy was diagnostic for a rare malignant peripheral nerve sheath tumor.

Clinical-Pathological Case Study Section Editors: Neil R. Miller, MD Janet Rucker, MD Five-Year-Old Boy With Behavioral Changes and Papilledema Radha Ram, MD, Jeremy Y. Jones, MD, Carrie A. Mohila, MD, PhD, Veeral S. Shah, MD, PhD Abstract: A 5-year-old boy had initial symptoms of behavioral changes, nausea, vomiting, headache, weight loss, and progressive vision failure. Brain MRI revealed abnormal signal intensity in both optic nerves, the optic chiasm, the right medial temporal lobe, and tissues surrounding the right supraclinoid internal carotid artery with associated leptomeningeal and spinal cord enhancement. After nondiagnostic dural and spinal arachnoid biopsies, a temporal lobe biopsy was diagnostic for a rare malignant peripheral nerve sheath tumor. Journal of Neuro-Ophthalmology 2018;38:75-80 doi: 10.1097/WNO.0000000000000562 © 2017 by North American Neuro-Ophthalmology Society Drs. Ram and Shah: A 5-year-old previously healthy boy, the product of a fullterm pregnancy and normal delivery, experienced subacute bilateral vision loss. He had received all appropriate immunizations, had no allergies, and was not on any medications. There was no family history of ocular or neurological diseases. On review of systems, the family denied fevers, rhinorrhea, and diarrhea. There was no history of recent travel or contact with sick individuals. Three months before presentation, the child developed increased agitation, somnolence, social withdrawal, discordant eye blinking, nausea, emesis, and headaches. As his symptoms Departments of Ophthalmology (RR, VSS), Radiology (JYJ), and Pathology (CAM), Baylor College of Medicine, Texas Children's Hospital, Houston, Texas. Supported in part by the clinical programs at Texas Children's Hospital-Baylor College of Medicine, Houston, TX. The authors report no conflicts of interest. Address correspondence to Veeral S. Shah, MD, PhD, Department of Ophthalmology, Baylor College of Medicine, Texas Children's Hospital, 6701 Fannin, Suite 610.25 Houston, Texas 77030; E-mail: [e-mail] Ram et al: J Neuro-Ophthalmol 2018; 38: 75-80 coincided with the beginning of the school year, his pediatrician initially diagnosed him with separation anxiety and stress-induced emesis. A few weeks later, however, he presented to an outside hospital with esotropia and bilateral blurred vision. Brain MRI revealed a large, right temporal tip arachnoid cyst but was otherwise interpreted as normal, and the patient was discharged home. He subsequently was evaluated by an ophthalmologist and was found to have bilateral optic disc swelling. Lumbar puncture revealed an opening pressure of 28 cm H2O and cerebrospinal fluid (CSF) analysis was unremarkable. He was started on acetazolamide solution (20 mg/kg/day) and underwent an image-guided right temporal craniotomy with arachnoid cyst fenestration. Immediately after surgery, his nausea, emesis, headaches, and esotropia resolved; however, 2 weeks later, he experienced a rapid decline in vision, mental status, and gait stability. Repeat MRI was performed, and the initial MRI was reviewed. Dr. Jones: The initial brain MRI shows multiple areas of enhancement including the prechiasmal segments of the optic nerve, the left trigeminal nerve, an area surrounding the right supraclinical internal carotid artery, and the leptomeninges. A right middle cranial fossa arachnoid cyst also is present (Fig. 1). An MRI performed postoperatively shows progression of the leptomeningeal disease (Fig. 2). Drs. Ram and Shah: An evaluation for both infectious and inflammatory disease was unremarkable. Testing included bartonella, HIV, herpes simplex virus, tuberculosis (PPD and QuantiFERON-gold), cryptococcus, coccidioidomycosis, histoplasmosis, blastomycosis, toxoplasmosis, and antinuclear antibodies, rheumatoid factor, angiotensin converting enzyme, p-ANCA, myelin basic protein, oligoclonal bands and immunoglobulin analysis. A repeat lumbar puncture demonstrated an opening pressure was .55 cm H2O with 75 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 1. Initial brain MRI. Postcontrast axial (A) and coronal (B) scans show a right middle fossa arachnoid cyst (arrowheads), enhancement of the prechiasmal optic nerves (black arrows) and optic discs (white arrows) and widespread leptomeningeal enhancement. C. There is a circumferential enhancement around the right supraclinoid internal carotid artery. D. Coronal T2 image reveals amorphous increased signal (arrows) in the right medial temporal lobe. normal CSF contents. Initial neuro-ophthalmologic examination revealed an alert, oriented, well-nourished boy in no acute distress but with meningismus. Visual acuity was 20/400, right eye, and 20/800, left eye. Visual fields were constricted with nasal islands of less than 10° in each eye. Motility and ocular alignment were normal. Pupils were large and sluggishly reactive to light. Intraocular pressures and anterior segment exams were normal. On ophthalmoscopy, there was marked optic atrophy in both eyes, with retinochoroidal shunt vessels in the right eye (Fig. 3). Neurological exam was otherwise unremarkable. Optic nerve sheath fenestration was attempted, but substantial engorgement of the ophthalmic vessels prevented successful completion of the procedure. Intraoperatively, repeat lumbar puncture again showed an opening pressure .55 cm H2O. Neurosurgery emergently placed an extraventricular drain and biopsied the dura. FIG. 2. MRI performed 3 months after onset of symptoms. Postcontrast axial scans show leptomeningeal enhancement (arrows) along the margins of the medial thalami (A) and left hemispheric sulci (B). 76 Ram et al: J Neuro-Ophthalmol 2018; 38: 75-80 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 3. Both optic discs appear pale with retinochoroidal shunt vessels present on the right optic disc and a peripapillary fluid ring in each eye. Dr. Mohila: The dural biopsy shows a fragment of benign dense connective tissue with no evidence of tumor or inflammation (Fig. 4). Drs. Ram and Shah: Postoperatively, the patient's vision improved to 20/200, right eye, and 20/400, left eye. The visual fields expanded to 30° in each eye. He was prophylactically started on broad spectrum antibiotics and steroids; however, with malignancy highest on the differential, repeat MRI of the brain and spine was performed. enhancement along the cord, best appreciated at the level of T6 and along the conus (Fig. 5). Drs. Ram and Shah: A spinal cord arachnoid biopsy was performed. Dr. Mohila: The spinal cord arachnoid biopsies show reactive changes with hypercellular foci (Fig. 6A, B) containing infiltrates of macrophages (Fig. 6C). An expanded panel of immunohistochemical stains was performed to determine whether a neoplastic process Dr. Jones: Repeat brain MRI showed changes similar to the previous MRI studies, with the exception of evidence of postoperative decompression of the right temporal arachnoid cyst. Spine MRI reveals multiple areas of leptomeningeal FIG. 4. Dural biopsy reveals benign collagenous tissue (hematoxylin & eosin, ·40). Ram et al: J Neuro-Ophthalmol 2018; 38: 75-80 FIG. 5. Postcontrast sagittal T1 spinal MRI. A. There is a leptomeningeal enhancement overlying the dorsal spinal cord (arrows) at T6. B. There is also leptomeningeal enhancement outlying the conus (arrow) extending to involve some of the dorsal upper lumbar nerve roots. 77 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 6. Spinal cord arachnoid biopsy is hypercellular (A and B) and contains an infiltrate of cells immunoreactive for CD68 (C), consistent with macrophages (A: hematoxylin & eosin, ·40; B: hematoxylin & eosin, ·200; and C: CD68, ·200). was present. Glial fibrillary acidic protein (GFAP), synaptophysin, smooth muscle antigen, desmin, leukocyte common antigen, and p53 are all negative. The Ki-67 proliferation indices in these hypercellular foci are low (less than 2%). Drs. Ram and Shah: A temporal lobe biopsy was performed. Dr. Mohila: The temporal lobe biopsy shows a hypercellular malignant infiltrative neoplasm composed of spindle and epithelioid cells (Fig. 7A, B). The epithelioid cells have abundant eosinophilic cytoplasm and pleomorphic nuclei with prominent nucleoli (Fig. 7C). Large bizarre and multinucleated tumor cells are scattered throughout the tumor. Immunohistochemical staining reveals the tumor cells are diffusely and strongly positive for S100 (Fig. 7D). A subset of the tumor cells shows cytoplasmic staining for epithelial membrane antigen (EMA) (Fig. 7E). Many show strong nuclear staining for p53 (Fig. 7F). The tumor cells are negative for GFAP, synaptophysin, multiple cytokeratins (pancytokeratin, high molecular weight, low molecular weight, CAM 5.2, CK7, and CK20), desmin, myogenin, CD43, CD34, and HMB-45. Mitotic figures including atypical forms are present. The Ki-67 proliferation index was elevated (up to 15%). This malignant spindle cell neoplasm with epithelioid features shows immunohistochemical features consistent with an epithelioid malignant peripheral nerve sheath tumor (MPNST). FIG. 7. Temporal lobe biopsy. There is a hypercellular neoplasm composed of spindle (A) and epithelioid cells (B). The epithelioid cells have abundant eosinophilic cytoplasm and marked nuclear pleomorphism with scattered large tumor cells that have hyperchromatic, irregular, and large nuclei (C). The tumor cells are diffusely and strongly positive for S100 (D). Subsets of tumor cells are positive for EMA (E) and p53 (F). (A and B: hematoxylin & eosin, ·200; C: hematoxylin & eosin, ·400; D: S100, ·200; E: EMA, ·200; and F: p53, ·200). EMA, epithelial membrane antigen. 78 Ram et al: J Neuro-Ophthalmol 2018; 38: 75-80 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study Final Diagnosis Epithelioid malignant peripheral nerve sheath tumor (MPNST) with leptomeningeal dissemination. Drs. Ram and Shah: The differential diagnosis of an intracranial tumor with leptomeningeal dissemination in a child of this age includes pilomyxoid astrocytoma (PMA), ganglioglioma, dysembryoplastic neuroepithelial tumor, fibrillary astrocytoma, and other glioneuronal tumors. In our patient, the initial neuroimaging appeared to be consistent with a PMA (1). PMAs are a more aggressive variant of pilocytic astrocytomas and commonly present in early childhood before 4 years of age (2). PMAs can have cystic components that often involve the temporal lobe, optic chiasm, and suprasellar regions of the brain (3). Our patient's brain biopsy was negative for GFAP, did not have areas of necrosis and hemorrhage, and was only weakly positive for synaptophysin, which collectively is uncharacteristic of PMA (4). Ultimately, the brain tissue biopsy confirmed a diagnosis of a MPNST. MPNSTs are rare and aggressive sarcomas that arise from the peripheral nerves or surrounding nerve sheath cells, such as Schwann cells, glial cells, perineural cells, and fibroblasts. MPNSTs account for 5%-10% of all sarcomas and commonly originate in peripheral nerves of the trunk and extremities but can sporadically arise from intracranial nerves (5,6). Most MPNSTs arise from normal peripheral nerves or pre-existing nerve sheath tumors, such as plexiform neurofibromas. Accordingly, the development of MPNSTs is closely associated with neurofibromatosis type I (NF1). It has been reported that approximately 50% of MPNSTs occur in NF1 patients with pre-existing neurofibromas. NF1 patients have a lifetime risk of 2%-10% for development of a MPNST (7,8). There are also several reported cases of benign tumors, neurofibromas, and schwannomas that have undergone malignant transformation with therapeutic radiation exposure (9-11). Our patient did not have any family history or clinical features of NF1, nor history of radiation exposure. Whole exome sequencing was performed on our patient and was negative for NF1 and NF2 gene mutations. The clinical manifestations of MNPSTs primarily depend on the peripheral nerve involved. A report of a 72-year-old with MNPST involved CNs II through VI, the sella, and both carotid arteries (12). L'heureux-Lebeau and Saliba (13) reviewed 60 patients with intracranial MPNSTs. Ages ranged from 3 to 75 years, with a maleto-female ratio of 1.5 to 1. The most commonly involved cranial nerves were CN VIII (60%), CN V (27%), and CN VII (10%). Cranial nerve VIII involvement resulted in hearing loss, imbalance, and vertigo. Patients with cranial nerve V involvement presented with facial pain, sensory paresthesia, weakened muscles of mastication, and abnormal corneal blink reflex. Extensive CSF dissemination can cause broad Ram et al: J Neuro-Ophthalmol 2018; 38: 75-80 neurological deficits, including cerebellar ataxia and elevated intracranial pressure (ICP) (8,10). Our patient initially presented with behavioral changes, unsteady gait, and symptoms of elevated ICP consistent with disseminated disease. MPNSTs are extremely aggressive malignant and invasive tumors that grow along nerves and infiltrate local tissue. Most peripheral MPNSTs metastasize hematogenously. The initial MRI findings in our patient demonstrated a right mesiotemporal arachnoid cyst with leptomeningeal enhancement of optic nerves, right carotid artery, and cranial nerve V (Fig. 1); however, the leptomeningeal disease initially was not recognized. Serial neuroimaging confirmed a primary tumor involving the right temporal lobe, diffuse intracranial leptomeningeal enhancement, and multifocal areas of leptomeningeal enhancement outlining the spinal cord and conus, most consistent with metastatic disease. Wasa et al (14) examined MRI features that differentiate MPNSTs from stable neurofibromas. The study retrospectively analyzed MRIs of 41 cases of MPNSTs and 20 cases of neurofibromas at 4 different institutions. Half of the MPNSTs arose from NF1-associated neurofibromas. Imaging characteristics for MPNSTs included intratumoral cystic changes, a perilesional edema-like zone, peripheral enhancement pattern, and the size of the mass. A meta-analysis reported 11 cases of intracranial MPNST in which 10 had spinal cord metastasis from pachymeningeal and/or leptomeningeal dissemination (14). Aside from the incidental arachnoid cyst, the MRI findings in our patient are consistent with previously reported cases. Although we cannot definitively confirm the original cranial nerve or localization of the MPNST, the initial MRI suggests cranial nerve V or the optic nerve as a plausible nidus. The diagnosis of an MPNST often is difficult, and requires an adequate biopsy. The immunohistochemical profile of the tumor cells (positive for S-100, vimentin, and EMA) in our patient was consistent with an epithelioid MPNST. The epithelioid variant of MPNST is a rare subtype with a prevalence of 5%-17% (15). The distinguishing immunohistochemical feature of epithelioid MPNSTs is diffuse strong immunoreactivity for S100, a feature not seen in other MPNSTs (16,17). The epithelioid variant also is less commonly associated with NF1, as was the case in our patient. MPNSTs are staged and treated as malignant soft-tissue sarcomas, and management of these locally advanced tumors is challenging. Because of its rarity, a consensus on treatment guidelines for patients with intracranial epithelioid MPNST has not been established. Current therapies are extrapolated from peripheral MPNST management. Most are treated with gross total resection followed by chemotherapy, radiation therapy, or both; although radiotherapy appears to play a pivotal role in MPNST (10), the role of chemotherapy remains controversial. In patients with elevated ICP, a ventriculoperitoneal shunt or external ventricular drain may be necessary. 79 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study The prognosis of intracranial MPNSTs is poor, with a median survival of 9 months, and a 1-year survival rate of 33% (13,18). In our patient, a ventriculoperitoneal shunt was placed and craniospinal radiation was recommended. Unfortunately, the patient survived for only a few months after palliative care was initiated. In summary, intracranial epithelioid MPSNTs are aggressive tumors that often present in their advanced stages. This pediatric case illustrates the difficulty in identifying this rare entity that may masquerade as a more common disease. The prominent arachnoid cyst, a developmental anomaly, directed attention away from imaging findings of leptomeningeal disease, resulting in delayed diagnosis. REFERENCES 1. Osborn AG, Salzman KL, Barkovich AJ. Pilomyoxid Astrocytoma. Diagnostic Imaging Brain, 2nd edition. New York, NY: Lippincott Williams & Wilkins, 2009. I.6-p34-37. 2. Ceppa EP, Bouffet E, Griebel R, Robinson C, Tihan T. The pilomyxoid astrocytoma and its relationship to pilocytic astrocytoma: report of a case and a critical review of the entity. J Neurooncol. 2007;81:191-196. 3. Chikai K, Ohnishi A, Kato T, Ikeda J, Sawamura Y, Iwasaki Y, Itoh T, Sawa H, Nagashima K. Clinico-pathological features of pilomyxoid astrocytoma of the optic pathway. Acta Neuropathol. 2004;108:109-114. 4. 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