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.

We provide a comprehensive clinical, radiological and virological analysis of four patients with Epstein-Barr virus (EBV) infection of the nervous system. One patient developed acute myeloradiculitis, one had acute encephalomyeloradiculitis, one had acute meningoencephalomyeloradiculitis and one had a subacute meningomyeloradiculitis. The ability of EBV to affect multiple parts of the entire neuraxis from meninges and brain to the spinal cord and peripheral nerves was evidenced by combinations of stiff neck and mental status changes, as well as patterns of weakness and sensory loss due to transverse myelitis or peripheral nerve disease. The CSF of all four patients contained a pleocytosis, predominantly mononuclear with elevated levels of protein, but a normal glucose level. In the two patients with acute myeloradiculitis and subacute meningomyeloradiculitis, the MRI revealed an increased signal in the spinal cord and lumbosacral roots, but in the two patients with acute encephalomyeloradiculitis and acute meningoencephalomyeloradiculitis, the brain and spinal cord MRIs were normal. In all four patients, EBV DNA, but not cytomegalovirus (CMV), herpes simplex virus (HSV) or varicella-zoster virus (VZV) DNA, was found in the CSF. The antibody pattern in serum was consistent with recent infection, and both EBV immunoglobulin (Ig) M and IgG antibodies, but not antibodies to HSV, VZV or CMV, were found in the CSF. Finally, there were reduced serum/CSF ratios of antibody to EBV, but not to total IgG or albumin, consistent with intrathecal antibody synthesis. None of the four patients died and none had brain swelling or focal changes according to brain MRI. Residual neurological deficits were evident. The two patients with acute myeloradiculitis and acute meningomyeloradiculitis had residual lower extremity weakness, and one of these patients later developed optic neuritis. The patient with acute encephalomyeloradiculitis had a moderate flaccid paraparesis, and the patient with subacute meningomyeloradiculitis was left with sensory loss in the feet. Compared with neurological disease caused by other herpes viruses, the clinical features of acute EBV myeloradiculitis, encephalomyeloradiculitis, encephalomyeloradiculitis and subacute meningomyeloradiculitis are distinctive. Of the eight human herpesviruses, EBV and VZV produce the most protean neurological syndromes. The mechanism by which EBV produces neurological disease is unknown. More correlative pathological, virological and immunological studies are needed in EBV-associated neurological disease.

Idiopathic sclerosing inflammation of the orbit is a distinct form of orbital inflammatory disease characterized by slow and relentless involvement of orbital structures. It is this insidious and relentless course that makes distinction from neoplastic lesions clinically difficult. We report the case of a patient with a several-week history of headache and decreased vision that was originally thought to represent an optic nerve sheath meningioma, based on clinical and radiographic evaluation. Subsequent histopathology from an optic nerve biopsy, however, was more consistent with optic nerve glioma. Eventually, pathologic examination of whole sections through the optic nerve was required to establish and confirm the actual diagnosis of sclerosing orbital inflammation.

The Controlled High Risk Avonex Multiple Sclerosis Study (CHAMPS) tested whether interferon beta la (Avonex) treatment would benefit patients who had experienced a first acute demyelinating event involving the optic nerve, brain stem/cerebellum, or spinal cord, and who displayed MRI brain signal abnormalities that have previously predicted a high likelihood of future MS-like events. The study randomized 383 patients into an Avonex-treated and a placebo-treated group; both groups received intravenous methylprednisolone 1 gm/d followed by prednisone 1 mg/kg for 11 days. The Avonex-treated group demonstrated a 44% reduction in the 3-year cumulative probability of developing clinically definite multiple sclerosis (rate ratio 0.56, 95% confidence interval 0.38 to 0.8; P = 0.002). At 18 months, treatment with Avonex was associated with a significant reduction of new T2 lesions, gadolinium enhanced lesions and T2 lesion volume. Among placebo-treated patients, 82% had developed a new subclinical MRI signal abnormality by the eighteenth month after study entry. Treatment benefit was observed irrespective of the qualifying event. The findings of this study support the efficacy of Avonex therapy in significantly reducing the 3-year likelihood of future neurologic events and worsening of the brain MRI in patients with a first acute CNS demyelinating event.

A 33-year-old man developed a complete third nerve palsy in the setting of acute bacterial endocarditis. MRI revealed an ischemic stroke in the cerebral peduncle involving the third nerve fascicle. Subsequently, he was observed to have paradoxic elevation of the eyelid on adduction and downgaze. To the authors' knowledge, this is the first demonstration of oculomotor synkinesis after an acquired, ischemic CNS lesion.

The authors report three patients with acute, chronic, and recurrent neuropathy associated with varicella zoster virus (VZV) infection but without zoster rash. CSF of all three patients contained VZV immunoglobulin G antibody, but not herpes simplex virus. In two patients, serum/CSF ratios of VZV immunoglobulin G were reduced compared to normal ratios for immunoglobulin G and albumin, and one patient also had VZV immunoglobulin M in CSF. All three patients received antiviral therapy and improved. The diagnosis of nervous system infection by VZV may be confirmed by the presence of antibody to VZV in CSF even without detectable VZV DNA.

Treatment decisions for ocular myasthenia gravis (OMG) should be based on symptomatology. Local, nonpharmacologic treatment of ptosis or diplopia is successful in relatively few patients, and the majority of patients require drug therapy for satisfactory resolution of their symptoms. Response to anticholinesterase agents is variable, but should always be used as the first-line agent or adjunctive therapy in the treatment of OMG. It is unknown whether early treatment of OMG with corticosteroids or other immunosuppressive agents prevents or delays the development of generalized myasthenia, although some observations support this speculation. Corticosteroids are usually necessary for adequate improvement of ophthalmoplegia or ptosis. Surgical correction of ptosis or ocular motility deficits is not recommended for most patients with OMG, because of the fluctuating nature of the deficits and the high rate of recurrent deficits following surgery. All patients with OMG should be screened for the presence of thymus tumors, and thymectomy is recommended for all patients with a thymoma. Some patients with OMG who do not harbor a thymus tumor may also benefit from thymectomy.

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.