Neuro-ophthalmic Mechanisms Of Disease

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Several neuro-degenerative diseases have characteristic eye movement abnormalities that can be used to diagnose and stage disease progression, and also be used as a bio-surrogate in therapeutic clinical trials. Often, eye movements studies help to gain insights into brain mechanisms. Eye movement recordings can be used to study short latency, small amplitude, reflexive eye movements to patterned targets which can help in understanding motion visual system. In collaboration with Boris Sheliga, Christian Quaia, and Bruce Cumming of the NEI, we continue to probe the visual motion system using ocular-following response techniques. These approaches use the machine-like eye movements subjects make in response to differing visual stimuli to help elucidate the mechanisms underlying motion and stereo vision. In the past year we studied short latency ocular following responses to visual motion stimuli that depend on the history of preceding stimuli and found that temporal modulation stimuli before the fixation period reduced the response of the subsequent ocular following. Also, preceding changes of illumination reduced the subsequent eye movement response. We characterized this suppression using different stimuli and determined the time course of the suppression. Also, by presenting transparent motion during the fixation period, we discovered a direction dependent component of the suppression. This study contributes to our understanding of motion vision. See Reference #1 Cohorts of patients with rare or unusual diseases are followed at NIH in natural history studies and many undergo neuro-ophthalmic exams. These studies help genotype-phenotype correlations and provide a basis for future interventional studies. Fibrous Dysplasia Fibrous dysplasia (FD) is a disease where normal bone is replaced with fibro-osseous tissue. Patients with McCune Albright syndrome (MAS) have polyostotic fibrous dysplasia, endocrine abnormalities, and cafe au lait spots. In McCune Albright syndrome, the anterior cranial base is frequently involved, including the sphenoid bones. The optic nerve passes through the sphenoid wing and is often found to be encased by FD on CT imaging. The management of fibrous dysplasia encased optic nerves is controversial, as optic neuropathy resulting in vision loss is the most frequently reported neurological complication. In collaboration with Dr. Michael Collins and Dr. Alison Boyce of the Dental Institute, a cohort of more than 100 patients with fibrous dysplasia continue to be followed longitudinally with neuro-ophthalmologic exams for over 20 years to track the natural history of this disease. Our experience in this cohort is that optic neuropathy is rare, and we recommend that surgical decompression not be done. However, patients with high growth hormone are at risk for optic neuropathy but only if the growth hormone excess is not controlled. In recent years we have observed some of our MAS patients exhibit optic disc edema, so we undertook to investigate the prevalence and potential clinical associations of optic disc edema in our MAS cohort. Optic disc edema was diagnosed in 7/187 subjects, for a prevalence of 3.7%. All subjects with optic disc edema were diagnosed before age 18 years and had mild, non-progressive disease. Radiographic structural abnormalities, including Chiari I malformation, aneurysmal bone cysts, and arachnoid cysts, were associated with higher odds of optic disc edema. Treatment with leuprolide, a gonadotropin releasing hormone analog, was also associated with optic disc edema. There was no significant association of optic disc edema with other MAS endocrinopathies, medications, optic canal diameter, or intracranial volume. In another study we reported on the quantitative measurements of intracranial volume, optic canal area, and peripapillary retinal nerve fiber layer (RNFL) of 124 patients with FD/MAS. Seven subjects had optic disc edema. A dataset of these measurements was created that can be used to assess typical ranges of these measures in the craniofacial FD/MAS population and to assess those ranges that are concerning for optic disc edema. See References #2 & #3 Cryptococcal meningoencephalitis Along with Dr. Peter Williamson and his NIAID team, we reported our experience in following patients with cryptococcal meningoencephalitis. Cryptococcal meningoencephalitis (CM) is a major cause of mortality in immunosuppressed patients and previously healthy individuals. In the latter, a post-infectious inflammatory response syndrome (PIIRS) is associated with a poor clinical response despite antifungal therapy and negative CSF cultures. 15 consecutive previously healthy patients with CM and PIIRS were treated with pulse corticosteroid taper therapy (PCT) consisting of intravenous methylprednisolone 1 gm daily for 1 week followed by oral prednisone 1 mg/kg/d, tapered based on clinical and radiological response plus oral fluconazole. Montreal Cognitive Assessments (MOCA), Karnofsky Performance scores, MRI brain scanning, ophthalmic and audiologic exams, and CSF parameters were compared at PIIRS diagnosis and after methylprednisolone completion. All patients demonstrated significant improvements in MOCA and Karnofsky scores at 1 month. All patients with papilledema and visual field deficits also exhibited improvement. The most common symptoms at PIIRS diagnosis were altered mental status and vision changes. In summary, PCT in this small cohort of PIIRS was associated with improvements in CM-related complications with minimal toxicity in the acute setting. See Reference #4 Ocular adverse effects of cancer treatment Many cancer treatments can have adverse effects on the eye. One example is MEK inhibitors which can cause retinal pigment elevations or subretinal fluid accumulations among other ocular effects. One example is Solumetinib that has proven to be very helpful in patients with neurofibromatosis type 1 that we follow in consult in the eye clinic. We have noted small foveal subretinal fluid deposits in several patients receiving Solumetinib, but these changes rarely affected vision and are also dose dependent. An extramural/intramural collaborative study at the NIH Clinical Center of patients with Moebius syndrome and related disorders is continuing under the leadership of Dr. Francis Collins and Dr. Irini Manoli, along with many other intramural and extramural collaborators. Several patients have been evaluated to date at NIH and other academic institutions. The goals include phenotype-genotype correlation of these patients who have unusual congenital extraocular muscle and cranial nerve problems. These patients all undergo complete neuro-ophthalmic assessment and often exome and other specialized genome sequencing, along with other testing to help characterize their disorder. Several papers have been published by this consortium. A recent paper describes a recognizable syndrome including congenital fibrosis of the intraocular muscles (CFEOM3), facial palsy, joint contractures and early onset peripheral neuropathy that is attributable to missense mutations in TUBB3 which encodes a neuron specific beta tubulin isotype. See Reference #6 We continue to study and follow the neuro-ophthalmic aspects of NIH study patients with Gaucher disease, CADASIL and associated vascular diseases, and other metabolic, neurodegenerative and neoplastic disease cohorts seen at NIH. See Reference #8