Revised Diagnosis From Histiocytic Neoplasm to Optic Chiasm Glioblastoma After Genetic Analysis.

ABSTRACT: A 46-year-old man presented with left eye blurring. Automated visual field testing showed an incongruous right hemianopia, with sparing of the lower temporal quadrant in the right eye. MRI revealed foci of gadolinium enhancement in the optic chiasm and optic tracts. Serologic testing (including myelin oligodendrocyte glycoprotein and neuromyelitis optica antibodies) and cerebrospinal fluid analysis were negative. Whole-body PET/CT scan found no malignancy. Biopsy of the optic chiasm revealed a moderately cellular neoplasm composed of atypical, discohesive cells with enlarged nuclei, prominent eosinophilic nucleoli, and abundant vacuolated cytoplasm. Immunohistochemical stains for CD68 and S100 were positive, whereas those for GFAP, OLIG2, SOX10, and multiple others were negative, supporting a diagnosis of histiocytic neoplasm. Five weeks later, results became available from next-generation sequencing targeting the coding regions of hundreds of malignancy-associated genes and select introns. Alterations associated with histiocytic neoplasms (i.e. BRAF and MAP2K1 mutations) were absent. However, there was a nonsense mutation in the PTEN gene, a hotspot mutation in the TERT gene promotor, and focal amplifications of the CDK4 and MDM2 genes. Additionally, there was chromosome 6q loss, 7 gain, and 10q loss. Based on these findings, the diagnosis was revised to glioblastoma, IDH-wildtype, CNS WHO grade 4. The patient began treatment with temozolomide while continuing radiation therapy. This case illustrates how next-generation sequencing can at times provide more accurate diagnostic information than standard tissue histopathology.

Permanent transduction of retinal ganglion cells by rAAV2-retro.

Adeno-associated virus (AAV) is widely used as a vector for delivery of gene therapy. Long term therapeutic benefit depends on perpetual expression of the wild-type gene after transduction of host cells by AAV. To address this issue in a mass population of identified single cells, 4 rats received an injection of a 1:1 mixture of rAAV2-retro-hSyn-EGFP and rAAV2-retro-hSyn-mCherry into each superior colliculus. After the virus was transported retrogradely to both retinas, serial fundus imaging was performed at days 14, 45, 211, and 375 to visualize individual fluorescent ganglion cells. The location of each cell was plotted to compare labeling at each time point. In 12/16 comparisons, 97% or more of the cells identified in the initial baseline fundus image were still labeled at day 375. In 4 cases the percentage was lower, but in these cases the apparent reduction in the number of labeled cells at day 375 was attributable to the lower quality of follow-up fundus images, rather than true loss of transgene expression. These data indicate that retinal ganglion cells transduced by rAAV2-retro are transduced permanently.

Postoperative magnetic resonance imaging of the inferior oblique muscle.

No previous imaging study has described the appearance of the inferior oblique muscle after surgery. It is unknown whether findings signifying prior myectomy or recession are recognizable on magnetic resonance (MR) imaging and how they might differ for the two procedures. After myectomy via a temporal approach, the cauterized muscle stump retracts into the medial orbit. How far it retracts and whether it reattaches to the globe remains unclear. To address these issues, orbital MR images were reviewed in 5 patients who had previously undergone inferior oblique myectomy or recession. In each case, the operated muscle exhibited subtle but telltale features, when compared with the normal, fellow inferior oblique. After myectomy, the inferior oblique still terminated lateral to the inferior rectus muscle and appeared closely apposed to the globe, although not necessarily attached to the sclera.

Decussating axons segregate within the anterior core of the primate optic chiasm.

BACKGROUND: The axons of ganglion cells in the nasal retina decussate at the optic chiasm. It is unclear why tumours cause more injury to crossing nasal fibres, thereby giving rise to temporal visual field loss in each eye. To address this issue, the course of fibres through the optic chiasm was examined following injection of a different fluorescent tracer into each eye of a monkey. METHODS: Under general anaesthesia, cholera toxin subunit B-Alexa Fluor 488 was injected into the right eye and cholera toxin subunit B-Alexa Fluor 594 was injected into the left eye of a single normal adult male rhesus monkey. After a week's survival for anterograde transport, serial coronal sections through the primary optic pathway were examined. RESULTS: A zone within the core of the anterior and mid portions of the optic chiasm was comprised entirely of crossing fibres. This zone of decussation was delineated by segregated, interwoven sheets of green (right eye) and red (left eye) fibres. It expanded steadily to fill more of the optic chiasm as fibres coursed posteriorly towards the optic tracts. Eventually, crossed fibres became completely intermingled with uncrossed fibres, so that ocular separation was lost. CONCLUSIONS: A distinct, central compartment located within the anterior two-thirds of the optic chiasm contains only crossing fibres. Sellar tumours focus their compressive force on this portion of the structure, explaining why they so often produce visual field loss in the temporal fields.

TRAF7 somatic mosaicism in a patient with bilateral optic nerve sheath meningiomas: illustrative case.

BACKGROUND: In the past decade, next-generation sequencing has spurred significant progress in the understanding of cytogenetic alterations that occur in meningiomas. Eighty percent of adult meningiomas harbor pathogenic somatic variants involving NF2, TRAF7, SMARCB1, KLF4, PI3K, or POLR2A. Somatic variants in TRAF7 associated with meningiomas usually localize to the gene's WD40 domains but are mutually exclusive to germline mutations, which cause a distinctive autosomal dominant syndrome. OBSERVATIONS: This case involved a 15-year-old girl with bilateral optic nerve sheath meningiomas, diffuse meningiomatosis, and syndromic features, including craniosynostosis, brain anomalies, syndactyly, brachydactyly, epicanthus, and patent ductus arteriosus. Genetic testing of the meningioma specimen 7 years after biopsy showed a pathogenic p.R641C variant within the WD40 domain of the TRAF7 gene. Additional testing of unaffected tissues identified the same variant at lower allele frequencies, consistent with postzygotic somatic mosaicism. LESSONS: The authors report postzygotic somatic mosaicism for a p.R641C variant in the TRAF7 gene in a patient with bilateral optic nerve sheath meningiomas, diffuse meningiomatosis and a constellation of systemic findings previously recognized in patients with germline mutations of this gene. This is the first report of optic nerve sheath meningioma in a patient with mutation in the TRAF7 gene.

Massive periorbital edema following hematopoietic stem cell transplantation.

Purpose: To describe a case of severe, bilateral periorbital edema after hematopoietic stem cell transplantation. Observations: A three-year old girl with metastatic neuroblastoma underwent the second of two tandem autologous peripheral blood stem cell transplants, complicated by engraftment syndrome. On post-engraftment day 11, she developed acute onset of severe periorbital edema. She was soon thereafter diagnosed with transplant-associated thrombotic microangiopathy with significant volume overload requiring treatment with eculizumab and etanercept. Periorbital edema resolved after four days with concurrent treatment of her underlying condition. Conclusions and Importance: We report an ocular manifestation related to complications of hematopoietic stem cell transplantation. This highlights a non-infectious etiology of eyelid swelling in the post-transplant, immunocompromised population.

Fundus imaging of retinal ganglion cells transduced by retrograde transport of rAAV2-retro.

Access of adeno-associated virus (AAV) to ganglion cells following intravitreal injection for gene therapy is impeded by the internal limiting membrane of the retina. As an alternative, one could transduce ganglion cells via retrograde transport after virus injection into a retinal target nucleus. It is unknown if recombinant AAV2-retro (rAAV2-retro), a variant of AAV2 developed specifically for retrograde transport, is capable of transducing retinal ganglion cells. To address this issue, equal volumes of rAAV2-retro-hSyn-EGFP and rAAV2-retro-hSyn-mCherry were mixed in a micropipette and injected into the rat superior colliculus. The time-course of viral transduction was tracked by performing serial in vivo fundus imaging. Cells that were labeled by the fluorophores within the first week remained consistent in distribution and relative signal strength on follow-up imaging. Most transduced cells were double-labeled, but some were labeled by only EGFP or mCherry. Fundus images were later aligned with retinal wholemounts. Ganglion cells in the wholemounts matched precisely the cells imaged by fundus photography. As seen in the fundus images, ganglion cells in wholemounts were sometimes labeled by only EGFP or mCherry. Overall, there was detectable label in 32-41% of ganglion cells. Analysis of the number of cells labeled by 0, 1, or 2 fluorophores, based on Poisson statistics, yielded an average of 0.66 virions transducing each ganglion cell. Although this represents a low number relative to the quantity of virus injected into the superior colliculus, the ganglion cells showed sustained and robust fluorescent labeling. In the primate, injection of rAAV2-retro into the lateral geniculate nucleus might provide a viable approach for the transduction of ganglion cells, bypassing the obstacles that have prevented effective gene delivery via intravitreal injection.

Damage to the Superior Retinae After 30 Gy Whole-Brain Radiation.

PURPOSE: The most common treatment protocol for whole-brain radiation therapy (WBRT) is 30 Gy in 10 fractions. This regimen entails a low risk of radiation retinopathy, with fewer than a dozen reported cases. We describe a case of radiation retinopathy that was confined to the superior retinae. These regions were the only portions of the eyes that were included in the treatment field. METHODS AND MATERIALS: Observational case report consisting of clinical examination, review of radiation treatment planning and implementation, computerized visual field testing, and fundus photography. RESULTS: A 36-year-old man with metastatic lung adenocarcinoma developed radiation retinopathy 16 months after WBRT to 30 Gy in 10 fractions. The retinopathy was largely confined to the superior halves of the retinae. There was corresponding geographic inferior visual field loss in both eyes. Review of the patient's treatment protocol revealed that the superior retinae received a substantial radiation dose, approaching 30 Gy, whereas the inferior retinae were essentially outside the treatment field. CONCLUSIONS: In this patient, the correlation between the treatment field and the resulting local development of radiation retinopathy demonstrated unequivocally that the relatively low dose used in routine WBRT (ie, 30 Gy in 10 fractions) can induce radiation retinopathy.

Papilledema from gain-of-function mutations in the STAT3 gene.

BACKGROUND: Signal Transducer and Activator of Transcription 3 (STAT3) gain-of-function germline mutations are associated with diverse clinical manifestations, including autoimmune cytopenia, lymphadenopathy, immunodeficiency, endocrinopathy, and enteropathy. We describe a new feature: raised intracranial pressure with papilledema. MATERIALS AND METHODS: Report of two cases. RESULTS: The first patient had a de novo heterozygous c.2144C>T (p.Pro715Leu) mutation in the STAT3 gene. At age 1 she had papilledema with marked sheathing of the proximal vessels on the optic discs. Follow-up 8 years later showed chronic papilledema, cystoid macular edema, and vision loss. The second patient had a de novo heterozygous c.2147C>T (p.Thr716Met) mutation. At age 12 he developed papilledema, which recurred despite treatment. In both patients, repeated sampling of the cerebrospinal fluid demonstrated a lymphocytic pleocytosis. CONCLUSIONS: Papilledema can occur as a manifestation of STAT3 gain-of-function mutation, sometimes accompanied by prominent vascular sheathing and cystoid macular edema. The mechanism may be chronic meningeal infiltration by white blood cells, impairing cerebrospinal fluid absorption.

Spontaneous Reattachment of the Medial Rectus After Free Tenotomy.

PURPOSE: To assess the outcome of free tenotomy of the medial rectus muscle in post-natal monkeys. METHODS: The medial rectus muscle was disinserted in both eyes of 6 macaques at age 4 weeks to induce an alternating exotropia. After the impact on the visual cortex and superior colliculus was investigated, the animals were examined post-mortem to assess the anatomy of the medial rectus muscles. RESULTS: After tenotomy, the monkeys eventually recovered partial adduction. Necropsy revealed that all 12 medial rectus muscles had reattached to the globe. They were firmly connected via an abnormally long tendon, but at the native insertion site. CONCLUSIONS: Medial rectus muscles are able to reattach spontaneously to the eye following free tenotomy in post-natal macaques. The early timing of surgery and the large size of the globe relative to the orbit may explain why reinsertion occurs more readily in monkeys than in children with a lost muscle after strabismus surgery. [J Pediatr Ophthalmol Strabismus. 2018;55(5):335-338.].

Bilateral Optic Disc Pits With Posterior Pituitary Ectopia.

Posterior pituitary ectopia has been reported previously in association with optic nerve hypoplasia, as a variant of septo-optic dysplasia. We describe a 14-year-old boy with posterior pituitary ectopia and bilateral optic disc pits. He had hypopituitarism and a reduction in visual acuity to 20/40 in each eye, owing to loss of foveal ganglion cells. Optic pits and posterior pituitary ectopia may have occurred together in the same subject by chance, but the rarity of both conditions suggests a possible association.

Diagnosis of Tensilon-Negative Ocular Myasthenia Gravis By Daily Selfie.

The initial symptoms of myasthenia gravis are usually ptosis and diplopia. The diagnosis is often confirmed by testing for anti-acetylcholine receptor antibodies or by observing the effects of intravenous edrophonium (Tensilon) injection. However, these standard tests may be negative in patients with isolated ocular findings. We present the case of an 83-year-old woman with negative serologic and Tensilon testing. She was asked to photograph herself daily. The resulting sequence of daily selfies captured striking fluctuations in her ocular alignment and ptosis. Daily selfies may be a useful strategy for confirming the clinical diagnosis of ocular myasthenia gravis.

Direct visualization of improved optic nerve pial vascular supply following tuberculum meningioma resection: case report.

Tuberculum sellae meningiomas frequently produce visual loss by direct compression from tumor, constriction of the optic nerve (ON) under the falciform ligament, and/or ON ischemia. The authors hypothesized that changes in visual function after tumor removal may be related to changes in blood supply to the ON that might be seen in the pial circulation at surgery. Indocyanine green (ICG) angiography was used to attempt to document these changes at surgery. The first patient in whom the technique was used had a left-sided, 1.4-cm, tuberculum meningioma. Time-lapse comparison of images was done postsurgery, and the comparison of video images revealed both faster initial filling and earlier complete filling of the ON pial circulation, suggesting improved pial blood flow after surgical decompression. In follow-up the patient had significant improvements in both visual acuity and visual fields function. Intraoperative ICG angiography of the ON can demonstrate measurable changes in pial vascular flow that may be predictive of postoperative visual outcome. The predictive value of this technique during neurosurgical procedures around the optic apparatus warrants further investigation in a larger cohort.

Contrasting effects of strabismic amblyopia on metabolic activity in superficial and deep layers of striate cortex.

To probe the mechanism of visual suppression, we have raised macaques with strabismus by disinserting the medial rectus muscle in each eye at 1 mo of age. Typically, this operation produces a comitant, alternating exotropia with normal acuity in each eye. Here we describe an unusual occurrence: the development of severe amblyopia in one eye of a monkey after induction of exotropia. Shortly after surgery, the animal demonstrated a strong fixation preference for the left eye, with apparent suppression of the right eye. Later, behavioral testing showed inability to track or to saccade to targets with the right eye. With the left eye occluded, the animal demonstrated no visually guided behavior. Optokinetic nystagmus was absent in the right eye. Metabolic activity in striate cortex was assessed by processing the tissue for cytochrome oxidase (CO). Amblyopia caused loss of CO in one eye's rows of patches, presumably those serving the blind eye. Layers 4A and 4B showed columns of reduced CO, in register with pale rows of patches in layer 2/3. Layers 4C, 5, and 6 also showed columns of CO activity, but remarkably, comparison with more superficial layers showed a reversal in contrast. In other words, pale CO staining in layers 2/3, 4A, and 4B was aligned with dark CO staining in layers 4C, 5, and 6. No experimental intervention or deprivation paradigm has been reported previously to produce opposite effects on metabolic activity in layers 2/3, 4A, and 4B vs. layers 4C, 5, and 6 within a given eye's columns.

Vertical diplopia and ptosis from removal of the orbital roof in pterional craniotomy.

PURPOSE: To describe a newly recognized clinical syndrome consisting of ptosis, diplopia, vertical gaze limitation, and abduction weakness that can occur after orbital roof removal during orbito-zygomatic-pterional craniotomy. DESIGN: Case series. PARTICIPANTS: Eight study patients (7 women), 44 to 80 years of age, with neuro-ophthalmic symptoms after pterional craniotomy. METHODS: Case description of 8 study patients. MAIN OUTCOME MEASURES: Presence of ptosis, diplopia, and gaze limitation. RESULTS: Eight patients had neuro-ophthalmic findings after pterional craniotomy for meningioma removal or aneurysm clipping. The cardinal features were ptosis, limited elevation, and hypotropia. Three patients also had limitation of downgaze and 2 patients had limitation of abduction. Imaging showed loss of the fat layers that normally envelop the superior rectus and levator palpebrae superioris. The muscles appeared attached to the defect in the orbital roof. Ptosis and diplopia developed in 2 patients despite Medpor titanium mesh implants. Deficits in all patients showed spontaneous improvement. In 2 patients, a levator advancement was required to repair ptosis. In 3 patients, an inferior rectus recession using an adjustable suture was performed to treat vertical diplopia. Follow-up a mean of 6.5 years later revealed that all patients had a slight residual upgaze deficit, but alignment was orthotropic in primary gaze. CONCLUSIONS: After pterional craniotomy, ptosis, diplopia, and vertical gaze limitation can result from tethering of the superior rectus-levator palpebrae superioris complex to the surgical defect in the orbital roof. Lateral rectus function sometimes is compromised by muscle attachment to the lateral orbital osteotomy. This syndrome occurs in approximately 1% of patients after removal of the orbital roof and can be treated, if necessary, by prism glasses or surgery.

Enlargement of the sella turcica in pseudotumor cerebri.

OBJECT: The sella turcica usually appears partially empty in MR images obtained from patients with chronic elevation of intracranial pressure. The authors measured the size of the sella turcica to determine if enlargement of the pituitary fossa explains the partially empty sella associated with pseudotumor cerebri. METHODS: The medical records from 2005 to 2011 of a single neuro-ophthalmologist were searched to identify consecutive patients with pseudotumor cerebri. Age-matched control patients were selected from the same practice. The sella turcica and pituitary gland were measured on sagittal T1-weighted MR images. RESULTS: Measurements were obtained for 48 patients with pseudotumor cerebri and 48 controls. The cross-sectional area of the sella was 38% greater in the patients with pseudotumor cerebri, with only a slight reduction in mean pituitary gland size. CONCLUSIONS: Chronic elevation of intracranial pressure is associated with bony enlargement of the sella turcica. Enlargement of the sella turcica contributes to its partially empty appearance.