Faculty Bibliography

PURPOSE: Idiopathic intracranial hypertension (IIH) is a disorder associated with increased intracranial pressure without evidence of a space-occupying lesion and with normal cerebrospinal fluid constituents. The disease is rare in the pediatric population. In this study, we assessed the visual outcome of children with IIH and the risk of recurrence. METHODS: This single-center observational retrospective cohort study included 90 children younger than 18 years of age who satisfied the modified Dandy criteria for the diagnosis of IIH. Upon follow-up, the treatment was discontinued when patients were free of symptoms such as headaches, transient visual obscurations or tinnitus, and when examination revealed no evidence of papilledema. The main outcome measures were visual acuity and visual field outcomes as well as risk of recurrence. RESULTS: The mean follow-up was 30.65 months (range 1.15-172.6 months, standard deviation 27.47 months). Special grading scales were devised for visual acuity and visual field scores. The mean visual acuity score improved from 4.7 +/- 0.62 to 4.87 +/- 0.44 (p = 0.003).The mean visual field score improved from 3.41 +/- 0.8 to 3.52 +/- 0.75 (p = 0.21). The recurrence rate was 23.7%, and the risk of recurrence was highest within the first 18 months after diagnosis of IIH. CONCLUSIONS: These study results suggest that pediatric patients with IIH have a favorable visual outcome in terms of both visual acuity and visual field. If there is any recurrence, it is most likely to occur during the first 18 months after diagnosis.

Axonal and neuronal degeneration are important features of multiple sclerosis (MS) and other neurologic disorders that affect the anterior visual pathway. Optical coherence tomography (OCT) is a non-invasive technique that allows imaging of the retinal nerve fiber layer (RNFL), a structure which is principally composed of ganglion cell axons that form the optic nerves, chiasm, and optic tracts. Since retinal axons are nonmyelinated until they penetrate the lamina cribrosa, the RNFL is an ideal structure (no other central nervous system tract has this unique arrangement) for visualizing the processes of neurodegeneration, neuroprotection and, potentially, even neuro-repair. OCT is capable of providing high-resolution reconstructions of retinal anatomy in a rapid and reproducible fashion and permits objective analysis of the RNFL (axons) as well as ganglion cells and other neurons in the macula. In a systematic OCT examination of multiple sclerosis (MS) patients, RNFL thickness and macular volumes are reduced when compared to disease-free controls. Conspicuously, these changes, which signify disorganization of retinal structural architecture, occur over time even in the absence of a history of acute demyelinating optic neuritis. RNFL axonal loss in MS is most severe in those eyes with a corresponding reduction in low-contrast letter acuity (a sensitive vision test involving the perception of gray letters on a white background) and in those patients who exhibit the greatest magnitude of brain atrophy, as measured by validated magnetic resonance imaging techniques. These unique structure-function correlations make the anterior visual pathway an ideal model for investigating the effects of standard and novel therapies that target axonal and neuronal degeneration. We provide an overview of the physics of OCT, its unique properties as a non-invasive imaging technique, and its potential applications toward understanding mechanisms of brain tissue injury in MS, other optic neuropathies, and neurologic disorders.

Optical coherence tomography studies in multiple sclerosis have primarily focused on evaluation of the retinal nerve fibre layer. The aetiology of retinal changes in multiple sclerosis is thought to be secondary to optic nerve demyelination. The objective of this study was to use optical coherence tomography to determine if a subset of patients with multiple sclerosis exhibit primary retinal neuronopathy, in the absence of retrograde degeneration of the retinal nerve fibre layer and to ascertain if such patients may have any distinguishing clinical characteristics. We identified 50 patients with multiple sclerosis with predominantly macular thinning (normal retinal nerve fibre-layer thickness with average macular thickness < 5th percentile), a previously undescribed optical coherence tomography defined phenotype in multiple sclerosis, and compared them with 48 patients with multiple sclerosis with normal optical coherence tomography findings, 48 patients with multiple sclerosis with abnormal optical coherence tomography findings (typical for multiple sclerosis) and 86 healthy controls. Utilizing a novel retinal segmentation protocol, we found that those with predominant macular thinning had significant thinning of both the inner and outer nuclear layers, when compared with other patients with multiple sclerosis (P < 0.001 for both), with relative sparing of the ganglion cell layer. Inner and outer nuclear layer thicknesses in patients with non-macular thinning predominant multiple sclerosis were not different from healthy controls. Segmentation analyses thereby demonstrated extensive deeper disruption of retinal architecture in this subtype than may be expected due to retrograde degeneration from either typical clinical or sub-clinical optic neuropathy. Functional corroboration of retinal dysfunction was provided through multi-focal electroretinography in a subset of such patients. These findings support the possibility of primary retinal pathology in a subset of patients with multiple sclerosis. Multiple sclerosis-severity scores were also significantly increased in patients with the macular thinning predominant phenotype, compared with those without this phenotype (n = 96, P=0.006). We have identified a unique subset of patients with multiple sclerosis in whom there appears to be disproportionate thinning of the inner and outer nuclear layers, which may be occurring as a primary process independent of optic nerve pathology. In vivo analyses of retinal layers in multiple sclerosis have not been previously performed, and structural demonstration of pathology in the deeper retinal layers, such as the outer nuclear layer, has not been previously described in multiple sclerosis. Patients with inner and outer nuclear layer pathology have more rapid disability progression and thus retinal neuronal pathology may be a harbinger of a more aggressive form of multiple sclerosis.

PURPOSE: To determine the relationship of high-contrast visual acuity (VA) and low-contrast letter acuity with retinal nerve fiber layer (RNFL) thickness in children with optic pathway gliomas. DESIGN: Cross-sectional convenience sample, with prospective data collection, from a tertiary care children's hospital of patients with optic pathway gliomas associated with neurofibromatosis type 1, sporadic optic pathway gliomas, and neurofibromatosis type 1 without optic pathway gliomas. METHODS: Patients underwent best-corrected VA testing using surrounded H, O, T, V optotypes and low-contrast letter acuity (5%, 2.5%, and 1.25% low-contrast Sloan letter charts). Mean RNFL thickness (micrometers) was measured by a Stratus optical coherence tomography device (Carl Zeiss Meditec) using the fast RNFL thickness protocol. Eyes were classified as having abnormal vision if they had high-contrast VA of more than 0.1 logarithm of the minimal angle of resolution units or visual field loss. The association of subject age, glioma location, and RNFL thickness with both VA and low-contrast letter acuity scores was evaluated by 1-way analysis of variance and linear regression, using the generalized estimating equation approach to account for within-patient intereye correlations. RESULTS: Eighty-nine eyes of patients with optic pathway gliomas were included, and 41 were classified as having abnormal VA or visual field loss. Reduced RNFL thickness was associated significantly with higher logarithm of the minimal angle of resolution scores for both VA (P < .001) and all low-contrast letter acuity charts (P < .001) when accounting for age and glioma location. CONCLUSIONS: Eyes of most children with optic pathway gliomas and decreased RNFL thickness had abnormal VA or visual field loss.

A 56-year-old man developed a pupil-involving left third nerve palsy. Imaging studies of the brain and intracranial vessels were normal. Neurological examination demonstrated a sensory polyneuropathy and mild distal weakness. Nerve conduction studies showed prolonged distal motor latencies. An enzyme-linked immunosorbent assay test detected high titers of anti-myelin-associated glycoprotein (MAG) antibodies. The patient improved with prednisone and rituximab treatment. Anti-MAG neuropathy should be considered when evaluating a patient with an undiagnosed cranial neuropathy, especially in the setting of a sensory neuropathy.

OBJECTIVE: To report the first histopathologic description of optic nerve demyelination from tacrolimus (FK 506) toxicity in the absence of toxic levels of tacrolimus in a patient presenting with asymmetric bilateral visual loss after 5 years of tacrolimus therapy. PATIENTS: We report a patient status post cardiac and renal transplantation who developed severe, progressive and asynchronous bilateral visual loss after prolonged treatment with tacrolimus. Orbital MRI showed an enlarged left optic nerve that enhanced with gadolinium. CONCLUSION: After extensive negative work up, biopsy of one optic nerve was performed. Microscopic analysis showed extensive demyelination in the absence of vasculitis, neoplastic or infectious etiologies. Our patient illustrates that demyelination of the optic nerve causing asynchronous vision loss can be associated with tacrolimus toxicity in the absence of toxic drug levels.

OBJECTIVE: To determine whether weight gain is associated with recurrence in idiopathic intracranial hypertension (IIH). METHODS: Medical records of adult patients with IIH seen between 1993 and 2009 at 2 university hospitals were reviewed to identify those with and without recurrence. Patients with documented height and weight at presentation and at subsequent visits were studied. The Wilcoxon rank sum test was used to compare mean body mass index (BMI) and percent weight change between the groups of patients with recurrence and without recurrence. The signed-rank test was used for comparing BMI within groups at the various time points. RESULTS: Fifty women with IIH were included in the analyses: 26 had IIH recurrence and 24 did not. Patients with recurrence had greater BMI at the time of recurrence compared to BMI at diagnosis (p = 0.02, signed-rank test). They also demonstrated a greater degree of weight gain between initial resolution and recurrence (BMI change +2.0 kg/m(2) [-1.5 to 10.8]) compared to patients without recurrence (-0.75 kg/m(2) [-35 to 3.6], p = 0.0009, Wilcoxon rank sum test). Patients without recurrence demonstrated stable weights (0%[95% CI -9.6 to 10.1%]), while patients with recurrence demonstrated a 6% weight gain ([-3.5 to 40.2%], p = 0.005), with an average rate of BMI gain of 1.3 kg/m(2)/year vs -0.96 kg/m(2)/year in those without recurrence. CONCLUSION: Patients with IIH recurrence had significant increases in BMI compared to patients without recurrence in this cohort. Patients with resolved IIH should be advised that weight gain may be a risk factor for IIH recurrence.

OBJECTIVE: Sports-related concussion has received increasing attention as a cause of short- and long-term neurologic symptoms among athletes. The King-Devick (K-D) test is based on measurement of the speed of rapid number naming (reading aloud single-digit numbers from 3 test cards), and captures impairment of eye movements, attention, language, and other correlates of suboptimal brain function. We investigated the K-D test as a potential rapid sideline screening for concussion in a cohort of boxers and mixed martial arts fighters. METHODS: The K-D test was administered prefight and postfight. The Military Acute Concussion Evaluation (MACE) was administered as a more comprehensive but longer test for concussion. Differences in postfight K-D scores and changes in scores from prefight to postfight were compared for athletes with head trauma during the fight vs those without. RESULTS: Postfight K-D scores (n = 39 participants) were significantly higher (worse) for those with head trauma during the match (59.1 +/- 7.4 vs 41.0 +/- 6.7 seconds, p < 0.0001, Wilcoxon rank sum test). Those with loss of consciousness showed the greatest worsening from prefight to postfight. Worse postfight K-D scores (r(s) = -0.79, p = 0.0001) and greater worsening of scores (r(s) = 0.90, p < 0.0001) correlated well with postfight MACE scores. Worsening of K-D scores by >/=5 seconds was a distinguishing characteristic noted only among participants with head trauma. High levels of test-retest reliability were observed (intraclass correlation coefficient 0.97 [95% confidence interval 0.90-1.0]). CONCLUSIONS: The K-D test is an accurate and reliable method for identifying athletes with head trauma, and is a strong candidate rapid sideline screening test for concussion.

OBJECTIVE: Retinal nerve fiber layer (RNFL) abnormalities detected by optical coherence tomography (OCT) are useful markers for axonal loss and visual dysfunction in multiple sclerosis (MS), but their role in routine clinical management is not well-studied. METHODS: Clinical and OCT examinations were performed on 240 patients attending a neurology clinic. Using OCT 5th percentile to define abnormal RNFL thickness, we compared eyes classified by neurologists as having optic atrophy to RNFL thickness, and afferent pupillary defect (APD) to RNFL thickness ratios of eye pairs. RESULTS: Mean RNFL thickness was less in eyes classified by neurologists as having optic atrophy (79.4 +/- 21 mum; n=63) vs those without (97.0 +/- 15 mum; n=417; p < 0.001, t test) and in eyes with an APD (84.1 +/- 16 mum; n=44) than without an APD (95.8 +/- 17 mum; n=436; p < 0.001). Physicians' diagnostic accuracy for detecting pallor in eyes with an abnormal RNFL thickness was 79% (sensitivity=0.56; specificity=0.82). Accuracy for detecting a RAPD in patients with mean RNFL ratio (affected eye to unaffected eye) <0.90 was 73% (sensitivity=0.30; specificity=0.86). Ability to detect visual pathway injury via assessment of atrophy and APD differed between neurologists. CONCLUSIONS: OCT reveals RNFL abnormality in many patients in whom eyes are not classified by neurologic examiners as having optic atrophy. Further study is needed to define the role of OCT measures in the context of examinations for optic atrophy and APD by neuroophthalmologists. OCT-measured RNFL thickness is likely to have an important future role in the clinical setting.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system and leading cause of disability in young adults. Vision impairment is a common component of disability for this population of patients. Injury to the optic nerve, brainstem, and cerebellum leads to characteristic syndromes affecting both the afferent and efferent visual pathways. The objective of this review is to summarize the spectrum of eye disorders in patients with MS, their natural history, and current strategies for diagnosis and management. We emphasize the most common disorders including optic neuritis and internuclear ophthalmoparesis and include new techniques, such as optical coherence tomography, which promise to better our understanding of MS and its effects on the visual system.