A 26-Year-Old Woman With Diplopia and Nystagmus

A 26-year-old woman presented for a routine contact lens evaluation but was found to have a subtle right sixth nerve paresis and adducting nystagmus of the left eye. She reported horizontal diplopia on far right gaze as well as subjective right- sided weakness and poor balance for 1 year. Brain and spinal MRI revealed multiple cystic lesions with variable enhancement throughout the posterior fossa and cervical spinal cord. These MRI findings were highly suspicious for an infectious central nervous system process, such as neurocysticercosis; however, primary or metastatic tumors were also important considerations. Tumor location and imaging characteristics were most helpful in differentiating among these etiologies. A brain biopsy ultimately established the diagnosis of a rosette-forming glioneuronal tumor.

Clinical-Pathological Case Study Section Editors: Daniel R. Gold, DO Marc Levin, MD, PhD A 26-Year-Old Woman With Diplopia and Nystagmus William J. Anderson, MD, Aseem Sharma, MD, Miguel A. Guzman, MD, Sophia M. Chung, MD Abstract: A 26-year-old woman presented for a routine contact lens evaluation but was found to have a subtle right sixth nerve paresis and adducting nystagmus of the left eye. She reported horizontal diplopia on far right gaze as well as subjective rightsided weakness and poor balance for 1 year. Brain and spinal MRI revealed multiple cystic lesions with variable enhancement throughout the posterior fossa and cervical spinal cord. These MRI findings were highly suspicious for an infectious central nervous system process, such as neurocysticercosis; however, primary or metastatic tumors were also important considerations. Tumor location and imaging characteristics were most helpful in differentiating among these etiologies. A brain biopsy ultimately established the diagnosis of a rosetteforming glioneuronal tumor. Journal of Neuro-Ophthalmology 2020;40:533–537 doi: 10.1097/WNO.0000000000000959 © 2020 by North American Neuro-Ophthalmology Society Drs. Anderson and Chung: A 26-year-old healthy woman presented for a routine eye examination for contact lens fitting when she was found to have a mild right eye abduction deficit. There was an adducting (presumably “gaze-paretic”) nystagmus of the left eye in right gaze. Nystagmus was not exhibited in other gaze position. Smooth pursuit movements and saccades were normal. The patient admitted to binocular horizontal diplopia on far right gaze and right-sided incoordination and subjective weakness for approximately 1 year. MRI of the brain was performed, prompting hospital admission for further evaluation and management. Departments of Ophthalmology (WJA, MAG, SMC), Pathology (MAG), and Neurology (SMC), Saint Louis University School of Medicine, St. Louis, Missouri; and Department of Radiology (AS), Washington University School of Medicine, St. Louis, Missouri. The authors report no conflicts of interest. Address correspondence to William J. Anderson, MD, Department of Ophthalmology, 320-B, 1755 South Grand Boulevard, St. Louis, MO 63104; E-mail: [e-mail] Anderson et al: J Neuro-Ophthalmol 2020; 40: 533-537 On further questioning, the patient complained of diplopia in the primary position with prolonged exercise, specifically after running 1 mile. There was no antecedent trauma, illness, or travel outside the country. The patient’s husband, with whom she lives, traveled to Honduras 4 years earlier. She denied headache, nausea, or vomiting. She also denied variability of diplopia, associated ptosis, or other visual symptoms. Neuro-ophthalmologic examination revealed 20/20 vision bilaterally and normal color vision. Pupillary examination was normal without relative afferent pupillary defect. Slit-lamp examination and fundus examinations were normal with pink optic nerves. External examination revealed mild weakness of the right orbicularis oculi muscles. Corneal sensation was slightly reduced in both eyes. Sensorimotor testing found her to be orthotropic in the primary position with an 8 prism diopter esotropia on right gaze associated with gaze-paretic nystagmus in the same direction. The remainder of the patient’s neurologic examination was unremarkable, with normal deep tendon reflexes, no ataxia, and no other focal deficits. Dr. Sharma: Outside brain MRI was reviewed and showed multiple T1hypointense and T2 hyperintense cystic lesions within the posterior fossa involving the cerebellar vermis, right cerebellar hemisphere, and brainstem (Fig. 1A, B). On postcontrast T1-weighted images, linear enhancement was seen along the margins of one of these lesions in the right cerebellar hemisphere (Fig. 1C). Some cystic lesions showed internal eccentric signal suspicious for scolices (Fig. 2), leading to a high suspicion for parasitic infection, specifically neurocysticercosis (NCC). MRI of the spine revealed similar intramedullary lesions involving the upper cervical spinal cord (Fig. 3). There were no lesions seen in the thoracic or lumbar spinal cord. Computerized tomography imaging of the head demonstrated a confluent area of calcification in the central aspect of the lone-enhancing right cerebellar lesion (Fig. 4). 533 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 1. Sagittal T1-weighted (A) and axial T2-weighted (B) MRI showing multiple intra-axial cystic lesions throughout the posterior fossa. Contrast-enhanced axial T1-weighted image (C) showing peripheral enhancement in only 1 of these lesions. Drs. Anderson and Chung: Several potential diagnoses should be considered to explain the multiple cystic lesions seen throughout the posterior fossa and cervical spinal cord on neuroimaging. Considerations include parasitic infection, primary central nervous system (CNS) neoplasm, metastatic tumor, tuberculoma, and neurosarcoidosis. A workup for possible parasitic infection, specifically NCC, was pursued given the presence of the questionable scolex visualized within multiple cysts. The patient’s husband was a potential infectious source of NCC given his travel history to an endemic region. An extensive infectious and autoimmune evaluation was unremarkable. The infectious workup included echinococcus, toxoplasmosis, HIV, and tuberculosis—all were negative. Stool evaluation for ova and parasites was similarly negative. Erythrocyte sedimentation rate was within normal limits. Cerebrospinal fluid (CSF) studies were deferred because of the potential for herniation given the lesion burden. Given the concern for NCC and the potential for a significant inflammatory response and side effects associated with its treatment, consultation with experts in NCC at the Centers for Disease Control and Prevention (CDC) was secured. Furthermore, the possibility of coenurosis secondary to Taenia multiceps, Taenia serialis, Taenia brauni, or Taenia glomerata was entertained as well. Serum testing for NCC with the enzyme-linked immunoelectrotransfer blot was sent to the CDC. After consultation with the CDC and reviews of the case with numerous specialties, there was growing skepticism for a parasitic lesion. Ultimately, 1 week after the initial presentation, a biopsy of the calcified cerebellar lesion was pursued for definitive diagnosis. membrane, and mild atypia. Intervening fine capillary vessels and numerous calcifications were seen (Fig. 5A, B). Based on these characteristics, along with a low tumor proliferation index (Ki-67 immunostain 3%–4%), a low-grade primary tumor was established. Epithelial differentiation and features of a highgrade neoplasm were absent, arguing against metastatic tumors. Typical features of primary CNS neoplasms may be astrocytic, oligodendroglial, ependymal, or mixed glial and neuronal. The tumor cells showed strong nuclear staining for Olig2 (Fig. 5C) and ATRX (retained) immunohistochemical stains, indicative of mixed glioneuronal differentiation of the tumor. Glial fibrillary acidic protein immunostain highlighted intervening tumor cell stroma and rare cytoplasm and processes (Fig. 5D). Synaptophysin was only weakly and focally positive, mostly on tumor cells around calcifications. CD34 highlighted only blood vessels. Immunohistochemical stain for neurofilaments revealed only rare entrapped axons with large central areas of tumor devoid of axonal entrapment. Neu-N and BRAF V600E immunostains were negative. The combined morphological and immunohistochemical staining distinguished this lesion from an ependymoma or astrocytoma. Although some cells showed oligodendroglioma-like features (Fig. 5A, B), the absence of 1p19q codeletion on the chromosomal microarray ruled this tumor out. The tumor cells showed glioneuronal differentiation with positive staining for Dr. Guzman: The brain biopsy showed a cellular neoplastic process composed of small, round to oval cells with scant cytoplasm. A parasitic or inflammatory process was ruled out based on the absence of parasitic structure or inflammation. The tumor cells’ nuclei demonstrate finely granular chromatin, smooth nuclear 534 FIG. 2. Axial T1-weighted MRI showing an eccentric signal within some of these cystic lesions, suggesting possible scolices (arrows) due to neurocysticercosis (A, B). Anderson et al: J Neuro-Ophthalmol 2020; 40: 533-537 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 3. Sagittal T2-weighted MRI of the cervical spine showing a cystic intramedullary lesion in the upper cervical cord. Olig2 and ATRX, leading to the diagnosis of a low-grade glioneuronal tumor (LGGNT). LGGNTs that exhibit this varied pattern of histologic growth include dysembryoplastic neuroepithelial tumor (DNET), papillary glioneuronal tumor (PGNT), and rosetteforming glioneuronal tumor (RGNT) (1). DNETs are characterized by oligodendrocyte-like cells cast in the background of mucin microcysts, creating the appearance of “floating neurons” not seen on our pathology. In addition, this tumor is almost exclusively found in the supratentorial region. PGNTs are histopathologically characterized by uniform glial cells forming pseudopapillae around hyalinized vascular cores, unlike the oligodendrocyte-like cells seen in our biopsy. This tumor is also most commonly found in the supratentorial regions, often in the temporal lobes. RGNTs show mixed glioneuronal differentiation with oligodendroglioma-like areas and are found nearly exclusively in the posterior fossa. The characteristic histological feature for RGNT is the presence of neurocytic rosettes with an eosinophilic core, although this feature was not present in our specimen. However, the overlapping histological characteristics along with the location of the tumor make RGNT the most likely diagnosis for this LGGNT. Final Diagnosis LGGNT most consistent with a RGNT. Drs. Anderson and Chung: Several factors delayed the correct diagnosis in the case: lack of significant symptoms despite the large space-occupying brain lesions, overlapping neuroradiographic features in our differential diagnoses, and the suggestion of the scolex Anderson et al: J Neuro-Ophthalmol 2020; 40: 533-537 FIG. 4. Computed tomography of the head showing a confluent region of calcification in the right cerebellar hemisphere. within multiple cysts. The duration and paucity of symptoms despite the lesion burden indicated a slow, indolent process. Visualization of the possible scolex on imaging led us to suspect a parasitic infection initially; however, a low-grade primary neoplasm remained on the differential. LGGNTs most commonly occur in the pediatric and young adult population. These tumors may present as multiple cystic lesions and can be difficult to distinguish from etiologies such as NCC. Both of these entities exhibit radiographic features that include cystic lesions, variable contrast enhancement, and calcifications (2,3). However, our case also highlights some important neuroimaging features that reflect the distinctly different natural progression of LGGNT and NCC. NCC lesions can present in various stages in the parasite lifecycle and exhibit various features reflective of the stage. In the vesicular stage, viable cysts appear isointense with the CSF, lack contrast enhancement, and show little to no surrounding inflammation. The scolex can be seen within the cysts at this stage and are highly indicative of a parasitic infection. As the parasites degenerate, pericystic contrast enhancement and edema are often observed. Eventually, cysts become nondetectable or may be replaced by punctate calcification (3). Although our case showed multiple cysts similar to NCC, many of these cysts were hyperintense to the CSF on fluid-attenuated inversion recovery images without 535 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 5. Histopathology of the cystic brain lesion: The tumor shows hyalinized vessels and calcifications (A, B, H&E, ·10). The tumor cells are small with round to oval nuclei and perinuclear clearing, giving it an “oligodendroglioma” appearance; however, 1p19q codeletion was not found (by chromosomal microarray). The tumor cells show positive staining for Olig2 (C) and retained ATRX immunostaining (not shown). Glial fibrillary acidic protein immunostaining was only positive in rare, intervening reactive astrocytes (D). exhibiting the edema or enhancement that often accompanies the colloid vesicular stage of NCC. Furthermore, the close geographic proximity of multiple intra-axial cystic lesions favors an intra-axial neoplastic process rather than the hematogenous spread of NCC. Finally, although calcifications frequently occur in NCC, they are often punctate (,5 mm) as opposed to a much larger focus of calcification as seen in our case, 12 mm (3). We believe this LGGNT to be most consistent with RGNT, a rare mixed glioneuronal tumor. The spectrum of these tumors has continued to expand since it was first introduced in the 2007 WHO classification of CNS tumors. Less than 200 cases of RGNT have been reported to date (4). These Grade 1 tumors arise most commonly from the midline along the fourth ventricle but have been reported in other locations, including but not limited to the cerebellum, supratentorial ventricular system, spinal cord, and brainstem. On MRI, RGNT classically appears as a T1-hypointense and T2hyperintense lesions with a variable solid-cystic architecture. Intravenous administration of a gadolinium-based contrast agent can show variable or no enhancement, and calcifications are present in approximately 25% of cases (2,5). On histopathology, these tumors exhibit a biphasic neurocytic and glial architecture. The neurocytic component includes rosettes formed around a synaptophysin-positive core (1). Several factors including the radiologic presentation, morphology, and location of the tumor make RGNT the leading differential diagnosis. Although the histopathological specimen did not show the most characteristic pathology, the neurocytic rosettes pathognomonic of RGNT can be focal and may have been missed on biopsy 536 or sectioning. Previous studies have shown biopsy accuracy to range between 51%-84% for low-grade gliomas (6). Other histopathological diagnoses to consider when suspecting LGGNT with varied patterned growth include DNET or PGNT (1). The multicystic radiologic appearance and posterior fossa location of this tumor supports RGNT over DNET or PGNT (5). FGFR1 and PIK3A genetic mutations have recently been associated with RGNT (7,8); however, gene sequencing of our specimen was not conducted. RGNTs typically present with symptoms and signs related to hydrocephalus, particularly headache, nausea/vomiting, and/or ataxia. Because the posterior fossa is most commonly affected, there is a wide variety of potential neuroophthalmologic signs. Before this case, to the best of our knowledge, only 1 other case reported nystagmus as a clinical finding (9). The average age of presentation is 28 years, with an equal distribution between men and women (4). Greater than 95% of RGNTs present as solitary masses. Excluding our case, there are only 8 reported cases with satellite lesions and 2 cases of dissemination (4). Overall, there is a good prognosis for these low-grade tumors. Only 4 reported cases have resulted in progression and death. The risk of tumor progression has been associated with only solid components, inadequate tumor resection, and pediatric age. Surgical resection is the preferred treatment for solitary tumors, but when there are multiple satellite lesions or dissemination, resection may not be feasible and radiation therapy may be considered to relieve symptoms. Our patient is currently being observed with follow-up MRI monitoring for tumor progression. At the 1-year follow-up, our patient subsequently developed a new rotary nystagmus in the primary position and gaze-evoked nystagmus in right, left, and down gaze. The patient is asymptomatic of oscillopsia in all positions of gaze and has diplopia only on far right gaze with a stable angle of ET; she is being conservatively followed. The patient is followed by neurosurgery and radiation oncology who has deferred radiation treatments because her lesion burden has been stable on follow-up MRI scans. In summary, RGNT is a rare mixed glioneuronal tumor with a predilection for the fourth ventricle and posterior fossa. The appearance of cystic lesions, calcification, and variable contrast enhancement can make the diagnosis difficult. The biopsy of the lesion ultimately confirms the diagnosis. REFERENCES 1. Tan CL, McLendon RE. Histological approach to neuronal and mixed neuronal-glial tumors of the central nervous system. J Glioma. 2018;1:89–96. 2. Gao L, Han F, Jin Y, Xiong J, Lv Y, Yao Z, Zhang J. Imaging features of rosette-forming glioneuronal tumours. Clin Radiol. 2018;73:275–282. 3. Zhao JLLA, Zheng S, Gao XJ, Zee CH. Imaging spectrum of neurocysticercosis. Radiology of Infectious Diseases. 2015;1:94–102. Anderson et al: J Neuro-Ophthalmol 2020; 40: 533-537 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study 4. Yang C, Fang J, Li G, Li S, Ha T, Wang J, Yang B, Yang J, Xu Y. Histopathological, molecular, clinical and radiological characterization of rosette-forming glioneuronal tumor in the central nervous system. Oncotarget. 2017;8:109175–109190. 5. Medhi G, Prasad C, Saini J, Pendharkar H, Bhat MD, Pandey P, Muthane Y. Imaging features of rosette-forming glioneuronal tumours (RGNTs): a Series of seven cases. Eur Radiol. 2016;26:262–270. 6. Pouratian N, Asthagiri A, Jagannathan J, Shaffrey ME, Schiff D. Surgery Insight: the role of surgery in the management of lowgrade gliomas. Nat Clin Pract Neurol. 2007;3:628–639. Anderson et al: J Neuro-Ophthalmol 2020; 40: 533-537 7. Gessi M, Moneim YA, Hammes J, Goschzik T, Scholz M, Denkhaus D, Waha A, Pietsch T. FGFR1 mutations in rosetteforming glioneuronal tumors of the fourth ventricle. J Neuropathol Exp Neurol. 2014;73:580–584. 8. Ellezam B, Theeler BJ, Luthra R, Adesina AM, Aldape KD, Gilbert MR. Recurrent PIK3CA mutations in rosette-forming glioneuronal tumor. Acta Neuropathol. 2012;123:285–287. 9. Jacques TS, Eldridge C, Patel A, Saleem NM, Powell M, Kitchen ND, Thom M, Revesz T. Mixed glioneuronal tumour of the fourth ventricle with prominent rosette formation. Neuropathol Appl Neurobiol. 2006;32:217–220. 537 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.