Faculty Bibliography

PURPOSE: To examine vision-specific health-related quality of life in a cohort of patients with multiple sclerosis (MS) using the 25-Item National Eye Institute Visual Function Questionnaire (VFQ-25), and to identify content areas for a brief MS-specific vision questionnaire. DESIGN: Cross-sectional survey. METHODS: The VFQ-25 and a modified version of the Optic Neuritis Treatment Trial (ONTT) Patient Questionnaire were administered by in-person interview to 80 patients at the University of Pennsylvania MS Center. Binocular visual acuities were obtained following a standard protocol using retroilluminated Early Treatment Diabetic Retinopathy Study charts. RESULTS: Despite a median binocular visual acuity of 20/16 (20/12.5-20/250), VFQ-25 subscale scores in the MS cohort were significantly lower (worse) compared with those of a published reference group of eye disease-free patients (P =.0001-0.009, two-tailed t tests). Rank-correlations of VFQ-25 composite (overall) scores with visual acuity were modest, but significant (r(s) = 0.33, P =.003), supporting construct validity for VFQ-25 scores in MS populations. Seven additional aspects of self-reported visual dysfunction in MS were also identified. CONCLUSIONS: Patients with MS have a high degree of self-reported visual dysfunction that is not entirely captured by visual acuity. The VFQ-25 is an effective measure of self-reported visual loss in MS. A brief MS-specific vision questionnaire may provide additional useful information when administered concurrently with the VFQ-25 in future investigations of MS and other neuroophthalmologic disorders.

Patients with typical acute monosymptomatic demyelinating optic neuritis should receive gadolinium-enhanced magnetic resonance imaging (MRI) of the brain and orbits to determine if they are at high risk for the subsequent development of clinically definite multiple sclerosis (CDMS). The presence of >or=2 white matter lesions (>or=3 mm in diameter, at least 1 lesion periventricular or ovoid) indicates high risk for CDMS; the following treatment should be considered for such patients: 1. Intravenous methylprednisolone sodium succinate (1 gram IV/day for 3 days) followed by oral prednisone (1 mg/kg/day for 11 days) with 4-day taper (20 mg on day 1, 10 mg on days 2 and 4); 2. Interferon beta 1-a (Avonex 30microg intramuscularly [IM] weekly, or Rebif 22 microg subcutaneously [SQ] weekly). These two drugs have been shown to reduce the short-term risk of CDMS in high risk monosymptomatic patients. In monosymptomatic patients with <2 white matter lesions, and in patients for whom CDMS has been established, IV methylprednisolone treatment followed by oral prednisone should be considered on an individual basis. Treatment in these patients may hasten visual recovery, but does not affect long-term visual outcome. Oral prednisone alone, without prior treatment with IV methylprednisolone, may increase the risk for recurrent optic neuritis and should be avoided.

The development of new and more sensitive clinical outcome measures for research in multiple sclerosis (MS) has been fueled by the development of effective therapies. As such, active arm comparison studies that require more sensitive clinical outcome measures are now commonplace. The Kurtzke Expanded Disability Status Scale (EDSS), the most widely used measure of neurologic impairment in MS, is particularly designed for classifying patients with respect to disease severity but has been criticized for its noninterval scaling, emphasis on ambulation status, relatively reduced sensitivity in the mid and upper ranges of scores, and absence of adequate cognitive and visual components. In response to perceived difficulties with the EDSS, the National Multiple Sclerosis Society Clinical Outcomes Assessment Task Force has developed the Multiple Sclerosis Functional Composite (MSFC). The MSFC includes three components that yield objective and quantitative results: 1) the timed 25-ft walk, 2) the nine-hole peg test, and 3) the 3-second paced auditory serial addition test. This scale has the advantages of continuous scoring with a composite Z score, standardized protocols, and high degrees of reliability and validity. Candidate visual function outcome measures for the MSFC, including the low-contrast Sloan letter chart, are currently under investigation. In addition to measures of neurologic impairment, health-related quality of life (HRQOL) measures have gained increasing importance as clinical trial outcome measures. The MS Quality of Life Inventory, a disease-specific HRQOL measure, has been developed to capture self-reported neurologic dysfunction and the impact of MS upon activities of daily living. MS clinical trials of the future, particularly active-arm comparison studies, will require more sensitive clinical outcome measures such as the MSFC. Measures of visual function and HRQOL should also be incorporated to capture the broad scope of neurologic impairment and disability in MS populations.

This review presents highlights and updates from of the most significant clinical trials in neuro-ophthalmology to date, the Optic Neuritis Treatment Trial, the Controlled High-Risk Avonex Multiple Sclerosis Prevention Study, and the Ischemic Optic Neuropathy Decompression Trial. The quality of evidence for treatment efficacy from these trials and other recent investigations of giant cell arteritis and idiopathic intracranial hypertension is classified herein according to published criteria based on sample size and study design.

This review highlights recent additions to the literature regarding the diagnosis, evaluation, and management of idiopathic intracranial hypertension (pseudotumor cerebri). Unique features of pediatric pseudotumor cerebri are addressed as well.

Patients with signs and symptoms consistent with acute monosymptomatic optic neuritis should undergo evaluation with gadolinium-enhanced MRI of the brain and orbits to determine whether or not they are at high risk for the development of clinically definite multiple sclerosis (CDMS). The presence of two or more white matter lesions (3 mm or larger in diameter, at least one lesion periventricular or ovoid) suggests high risk for CDMS, and should prompt immediate treatment as follows: Intravenous methylprednisolone sodium succinate (1 g intravenously per day for 3 days) followed by oral prednisone (1 mg/kg per day for 11 days) with a 4-day taper (20 mg on day 1, 10 mg on days 2 and 4). Interferon beta 1-a, which has been demonstrated to significantly reduce the 3-year probability of the development of CDMS and the development of clinically silent MRI lesions in high-risk patients with acute optic neuritis, should be considered following IV methylprednisolone treatment (30 &mgr;g intramuscularly weekly). In monosymptomatic patients with fewer than two white matter lesions by MRI, and in patients for whom a diagnosis of CDMS has been established, treatment with IV methylprednisolone followed by oral prednisone (as outlined), should be considered on an individual basis and may hasten visual recovery, but has not been demonstrated to affect long-term visual outcome. In all cases of typical acute monosymptomatic demyelinating optic neuritis, oral prednisone alone at a dose of 1 mg/kg per day, without prior treatment with IV methylprednisolone (1 g per day for 3 days), may increase the risk for recurrent optic neuritis, and should be avoided.

We report two patients who developed isolated visual symptoms and signs as initial manifestations of Creutzfeldt-Jakob disease (CJD). Both patients had normal conventional T1- and T2-weighted brain magnetic resonance (MR) images; in one patient, early cortical abnormalities were detected by diffusion-weighted and fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI). Results from the cerebrospinal fluid assay for the 14-3-3 brain protein were also negative in one patient, despite pathologic confirmation of CJD at autopsy. The Heidenhain variant of CJD should be considered in all patients who present with isolated visual manifestations, including homonymous hemianopsia and normal conventional brain MRI. Diffusion-weighted and FLAIR MRI may demonstrate early cortical abnormalities in patients with CJD. The CSF assay for the 14-3-3 protein may be normal, even in pathologically confirmed cases.

PURPOSE: To examine the potential for visual acuity loss, and its relation to extent and location of optic pathway gliomas in a cohort of children with neurofibromatosis type 1 studied with magnetic resonance imaging. METHODS: We reviewed the neuro-ophthalmologic records and brain/orbital magnetic resonance imaging scans for 43 consecutive pediatric patients with neurofibromatosis type 1 and optic pathway gliomas who were followed at the Children's Hospital of Philadelphia. The presence of visual loss, defined as abnormal visual acuity for age in one or both eyes, was determined. Optic pathway gliomas were classified by tumor extent and location according to involvement of the optic nerves, chiasm, and postchiasmal structures by magnetic resonance imaging. RESULTS: Involvement of the optic tracts and other postchiasmal structures at tumor diagnosis was associated with a significantly higher probability of visual acuity loss (P =.048, chi-square test). Visual loss was noted in 20 of 43 patients (47%) at a median age of 4 years; however, three patients developed visual acuity loss for the first time during adolescence. CONCLUSIONS: In pediatric patients with neurofibromatosis type 1 and optic pathway gliomas, the likelihood of visual loss is dependent on the extent and location of the tumor by magnetic resonance imaging and is particularly associated with involvement of postchiasmal structures. Furthermore, older age during childhood (adolescence) does not preclude the occurrence of visual loss. Close follow-up beyond the early childhood years, particularly for those with postchiasmal tumor, is recommended.

We describe a 45-year-old man with biopsy proven cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). This patient demonstrated unique retinal findings, including arteriole narrowing and sheathing, irregular choroidal filling on fluorescein angiography, and patchy visual field loss. CADASIL is a hereditary, nonamyloid, nonathersclerotic microangiopathy. This disorder has been mapped to chromosome 19 with mutations in the Notch 3 gene. Deposits of granular osmiophilic material in the basal lamina of the smooth muscle cells of small vessels are considered pathognomonic for CADASIL and are typically seen only on electron microscopy. Although CADASIL is a systemic vascular disease affecting the entire arteriole tree, we are unaware of other reports describing the retinal findings observed in our patient.

Neuro-ophthalmologic disorders, affecting the afferent and efferent visual systems, are frequently encountered by ophthalmologists in clinical practice. This article focuses on aspects of ocular, orbital, and neuroanatomy that are most important to the diagnosis of afferent and efferent visual pathway lesions. The use of optic disc and fundus appearance, visual fields, and ocular motility and pupillary findings are emphasized in the discussions of topographical diagnosis.