Visual deficits and cognitive assessment of multiple sclerosis: confounder, correlate, or both?

BACKGROUND: The relationship between visual impairment and cognitive performance in multiple sclerosis (MS) remains poorly understood. OBJECTIVE: To determine associations between visual acuity and optical coherence tomography (OCT) measures with cognitive performance of MS patients and healthy controls (HCs). METHODS: 141 MS patients (with and without MS optic neuritis; MSON) and 50 HCs underwent neuropsychological, visual, and OCT testing. California Verbal Learning Test (CVLT-II), Brief Visuospatial Memory Test (BVMT-R), and Symbol Digit Modalities Test (SDMT) were used. Patients with test performance below - 1.5 standard deviations of the mean HCs scores were labeled as cognitive impairment. Visual ability was assessed with 100%, 2.5%, and 1.25% low-contrast letter acuity (LCLA) charts. OCT-derived peripapillary retinal nerve fiber layer (pRNFL) thickness, macular volume (MV), macular ganglion cell inner plexiform (mGCIP) thickness (as a sum of GC and IP layers), and macular inner nuclear layer (mINL) were computed. RESULTS: 100% and 2.5% LCLA associated with SDMT in MS and HCs (p < 0.001; and p < 0.012, respectively). In MSON patients, visually demanding tests were explained by pRNFL and macular volume for SDMT (ß = 0.172, p = 0.039 and ß = 0.27, p = 0.001) and MV for BVMT-R (ß = 0.21, p = 0.012). In non-MSON, only mINL was predictor of CVLT-II. pRNFL and MV predicted cognitive impairment with an accuracy of 72.2% (Negelkerke R2 = 0.234). These findings were driven by associations within the progressive MS subgroup. HC's SDMT performance was explained by mGCIP (ß = 0.316, p = 0.001). CONCLUSIONS: Both LCLA and OCT-based measures (pRNFL and macular volume) were associated with MS cognitive performance. OCT-based measures were also significant predictors of cognitive status in MS patients. mGCIP associated with cognitive performance in HCs.

Serum neurofilament light chain and optical coherence tomography measures in MS: A longitudinal study.

OBJECTIVE: To study the association between serum neurofilament light chain (sNfL) and multiple optical coherence tomography (OCT) measures in patients with MS and healthy controls (HCs). METHODS: In this prospective study, 110 patients with MS were recruited, together with 52 age- and sex-matched HCs. Clinical evaluation and spectral domain OCT and sNfL were obtained at baseline and after 5.5 years of follow-up. Nested linear mixed models were used to assess differences between MS vs HC and associations between sNfL and OCT measures. Partial correlation coefficients are reported, and p values were adjusted for the false discovery rate. RESULTS: At baseline, peripapillary retinal nerve fiber layer thickness (pRNFLT) and macular ganglion cell and inner plexiform layer thickness (mGCIP) were significantly lower in MS than HC both in MS-associated optic neuritis (MSON) (p = 0.007, p = 0.001) and nonaffected MSON (n-MSON) eyes (p = 0.003, p = 0.018), along with total macular volume (TMV) in n-MSON eyes (p = 0.011). At follow-up, MS showed significantly lower pRNFLT, mGCIP, and TMV both in MSON and n-MSON eyes (p < 0.001) compared with HC. In MS n-MSON eyes, sNfL was significantly associated with baseline pRNFLT and mGCIP (q = 0.019). No significant associations were found in MSON eyes. CONCLUSIONS: This study confirms the ability of sNfL to detect neurodegeneration in MS and advocates for the inclusion of sNfL and OCT measures in clinical trials. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that sNfL levels were associated with MS neurodegeneration measured by OCT.

Retinal Arterio-Arterial Collaterals in Susac Syndrome.

BACKGROUND: The ophthalmic findings of Susac syndrome (SS) consist of visual field defects related to branch retinal artery occlusion (BRAO), and fluorescein angiography (FA) reveals a unique staining pattern. To date, retinal arterial collateral development has been described only in a single patient. Given that the immunopathological process in SS induces retinal ischemia, it is conceivable that abnormal blood vessel development may occur in affected individuals. METHODS: This is a retrospective observational study. The medical records including fundus photography and FA of all patients with SS were reviewed, and those with any type of retinal arterial collateral were identified. RESULTS: A total of 11 patients were identified with retinal collaterals. Five were men. Age ranged from 20 to 50 years. Ten patients had arterio-arterial (A-A) collaterals and 1 had arterio-venous (A-V) collaterals, and all had collaterals remote from the optic disc. No collaterals were present at onset of illness and the first developed at 9 months. CONCLUSIONS: The literature reveals scant evidence for the association between BRAO and retinal arterial collaterals. Our findings indicate that retinal arterial collaterals in SS are usually A-A and not A-V and may be more common in this disorder than previously believed. Collaterals do not develop early in the disease, and there may be a predilection toward development in men. The chronic inflammatory state of SS may be the stimulus for the development of these arterial collaterals.

Is Multiple Sclerosis Associated With a Lower Intraocular Pressure?

OBJECTIVE: To determine if multiple sclerosis (MS) is associated with lower intraocular pressure (IOP) compared with individuals without MS. METHODS: Thirty patients with clinically definite MS were identified and a retrospective chart review was conducted. Each patient with MS underwent IOP recording by a single investigator using kinetic applanation tonometry. Measurement of central corneal thickness (CCT) also was obtained. Similarly, 30 study controls were identified and kinetic applanation tonometry and CCT were recorded. Univariate analysis of covariance was conducted to determine a statistically significant difference between IOP between MS and control groups, controlling for age. RESULTS: Analyses were adjusted for age and 2 subjects were excluded because of steroid use. The average IOP in MS group was 12.3 mm Hg (right eye = 12.3 mm Hg, left eye = 12.2 mm Hg) and in the control group was 17 mm Hg (right eye = 16.9 mm Hg, left eye = 17 mm Hg). There was a significant effect of presence of MS on IOP accounting for 53% variability in mean IOP (F(1,55) = 60.7; P < 0.001) when compared with the control group. CONCLUSIONS: This study demonstrated that IOP was significantly lower in patients with MS compared with controls. A more in-depth prospective study design is required, along with further investigation of possible etiologies. Identifying the mechanism of decreased IOP in patients with MS might allow development of new-targeted therapies for the treatment of glaucoma.

Exudative Polymorphous Vitelliform Retinopathy: Importance of Early Recognition of the Condition in Patients with Metastatic Melanoma.

INTRODUCTION: Because of the advent of monoclonal antibodies in the treatment of metastatic melanoma, patients with this disease are surviving longer. Early recognition of the disease has therefore become even more important. CASE REPORT: We present a patient with vitelliform maculopathy, a paraneoplastic retinal maculopathy that is under-recognized. Clinically the retinal findings of serous detachments and pigmentary macular changes are remarkable, while at the same time these patients have surprisingly very few symptoms. This is in contrast to patients who develop melanoma associated retinopathy (MAR) who are very symptomatic early in the disease, but with more subtle retinal findings. CONCLUSION: Monoclonal antibody treatment is changing the survival rates in metastatic disease making early diagnosis even more important. Exudative polymorphous vitelliform maculopathy (EPVM) needs to be recognized early to avoid delay in diagnosis of metastatic disease.

Retinal nerve fiber thickness and MRI white matter abnormalities in healthy relatives of multiple sclerosis patients.

OBJECTIVES: To compare retinal nerve fiber (RNFL) thickness and conventional and non-conventional MRI characteristics of healthy controls (HCs) from the general population (non-fHC) to healthy relatives of multiple sclerosis (MS) patients (fHC). METHODS: Sixty-eight (68) HCs underwent optical coherence tomography (OCT) and 3T MRI examination. Subjects were classified based on whether or not there was a family history of MS. The study enrolled 40 non-fHC who had no relatives with MS and 28 fHC with at least one relative affected with MS. The associations between OCT parameters and conventional and non-conventional MRI measures were investigated. RESULTS: There were no significant OCT or conventional and non-conventional MRI measureable differences between the non-fHC and fHC groups. Periventricular localization and total volume of white matter (WM) signal abnormalities (SA) were more common in the fHC group but the differences did not reach a level of significance. A significant association between decreased RNFL thickness with increased volume (p=0.001), number (p=0.003) and frequency of ≥ 9 T2 (p=0.003) WM SAs on MRI was found in the fHC group. No association between OCT and MRI parameters was detected in the non-fHC group. CONCLUSION: There is an association between decreased RNFL thickness on OCT and increased WM injury in healthy relatives of MS patients. Further studies should explore the pathophysiology of these findings.

Neurological basis for eye movements of the blind.

When normal subjects fix their eyes upon a stationary target, their gaze is not perfectly still, due to small movements that prevent visual fading. Visual loss is known to cause greater instability of gaze, but reported comparisons with normal subjects using reliable measurement techniques are few. We measured binocular gaze using the magnetic search coil technique during attempted fixation (monocular or binocular viewing) of 4 individuals with childhood-onset of monocular visual loss, 2 individuals with late-onset monocular visual loss due to age-related macular degeneration, 2 individuals with bilateral visual loss, and 20 healthy control subjects. We also measured saccades to visual or somatosensory cues. We tested the hypothesis that gaze instability following visual impairment is caused by loss of inputs that normally optimize the performance of the neural network (integrator), which ensures both monocular and conjugate gaze stability. During binocular viewing, patients with early-onset monocular loss of vision showed greater instability of vertical gaze in the eye with visual loss and, to a lesser extent, in the normal eye, compared with control subjects. These vertical eye drifts were much more disjunctive than upward saccades. In individuals with late monocular visual loss, gaze stability was more similar to control subjects. Bilateral visual loss caused eye drifts that were larger than following monocular visual loss or in control subjects. Accurate saccades could be made to somatosensory cues by an individual with acquired blindness, but voluntary saccades were absent in an individual with congenital blindness. We conclude that the neural gaze-stabilizing network, which contains neurons with both binocular and monocular discharge preferences, is under adaptive visual control. Whereas monocular visual loss causes disjunctive gaze instability, binocular blindness causes both disjunctive and conjugate gaze instability (drifts and nystagmus). Inputs that bypass this neural network, such as projections to motoneurons for upward saccades, remain conjugate.

Novel treatment for radiation optic neuropathy with intravenous bevacizumab.

Radiation optic neuropathy is a devastating form of vision loss that can occur months to years after radiation therapy for tumors and other lesions located in close proximity to the visual pathways. We present the case of a 24-year-old woman who underwent external beam radiation for treatment of a tectal pilocytic astrocytoma, and 5 years later she developed bilateral radiation optic neuropathy and radiation necrosis of the right temporal lobe. We opted to treat her with intravenous bevacizumab with 3 doses every 3 weeks, as well as dexamethasone and pentoxifylline. After the first infusion of bevacizumab, the patient noted improvement in vision and color vision, and a follow-up magnetic resonance imaging study showed that the previous enhancement of the optic nerves and chiasm was diminishing. Her vision improved dramatically and has remained stable over a 3-year period.

Toluene optic neurotoxicity: magnetic resonance imaging and pathologic features.

Toluene, a colorless liquid found in glues, paints, and industrial products, is lipid soluble and rapidly absorbed by the lipid-rich central nervous system. Prolonged exposure through occupation or purposeful inhalation may lead to neurologic abnormalities. Two men presented with multifocal central nervous system defects and bilateral optic neuropathy of unclear etiology. After numerous diagnostic tests, including brain magnetic resonance imaging, lumbar puncture, hematologic studies, and in one patient a brain biopsy, chronic inhalation of toluene was found to be the cause. Timely diagnosis is important because patients may experience improvement in neurologic and ocular manifestations with cessation of exposure, whereas continued inhalant abuse or exposure can result in permanent loss of neurologic function.

Retinal nerve fiber layer thickness is associated with brain MRI outcomes in multiple sclerosis.

Multiple sclerosis is characterized by the dual pathological processes of inflammation and neurodegeneration. Conventional MRI techniques are considered the best tools for assessing and monitoring lesion burden and inflammation but are limited in their ability to assess axonal loss. Optical coherence tomography (OCT) is a simple high-resolution technique that uses near infrared light to quantify the thickness of the retinal nerve fiber layer (RNFL), which contains only non-myelinated axons. RNFL thickness (RNFLT) was measured using OCT on thirty consecutive MS patients (60 eyes). Eighteen patients underwent quantitative MRI analysis including T1- and T2-lesion volumes (LV), normalized brain volume (NBV), normalized cortical, white and gray matter volumes (NCV, NWMV, and NGMV), and mean whole brain diffusivity (MD). There was a strong association between NBV and average RNFL thickness (p<0.001, partial rp=0.77). The T2-LV and NWMV were significantly associated with average RNFL thickness (p=0.002, partial rp= -0.76 and p=0.005, partial rp=0.68, respectively) and there were trends toward association with T1-LV (p=0.041) and NGMV (p=0.067). There was negative correlation between average RNFL thickness (average of both eyes) and disability as assessed by EDSS (p=0.02). The results support potential usefulness of OCT for MS patient monitoring and research applications.

Study of mitoxantrone for the treatment of recurrent neuromyelitis optica (Devic disease).

BACKGROUND: Neuromyelitis optica is a severe demyelinating disease that selectively involves the optic nerves and the spinal cord but usually spares the brain. It is considered to have a B-cell-induced pathogenesis. Mitoxantrone hydrochloride, a synthetic anthracenedione approved for worsening relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis, has been shown to primarily suppress the humoral response. OBJECTIVE: To evaluate the benefit of mitoxantrone treatment in patients with relapsing neuromyelitis optica. DESIGN: Prospective 2-year study. SETTING: Academic multiple sclerosis center. PATIENTS: Five patients (3 women and 2 men) with an age range of 20 to 51 years and an Expanded Disability Status Scale score of 2.5 to 6.5 (mean +/- SD, 4.40 +/- 1.88). INTERVENTIONS: Monthly intravenous infusions of mitoxantrone hydrochloride, 12 mg/m2, for 6 months followed by 3 additional treatments every 3 months. MAIN OUTCOME MEASURES: Expanded Disability Status Scale score measured every 3 months and during relapses; findings on orbital, brain, and spinal cord magnetic resonance images performed at baseline and at 3, 6, 12, 18, and 24 months; and visual evoked potentials and results of ophthalmologic evaluations performed at baseline and annually. RESULTS: During the 2 years of treatment, 2 patients each had a relapse once within the initial 5 months of treatment (1 severe and 1 moderate). Improvement was seen clinically and on magnetic resonance images in 4 patients. Patients generally tolerated the treatment well, although 1 patient had a reversible decrease in cardiac ejection fraction. CONCLUSION: Our results suggest a beneficial effect of mitoxantrone treatment for relapsing neuromyelitis optica.

Treatment of chronic facial pain.

Facial pain occurs because of damage to the fifth cranial nerve anywhere along its course from its terminal subcutaneous craniofacial branches to the brainstem. Although topical agents may be effective in relieving pain caused by subcutaneous branch damage, systemic oral agents are usually needed to alter or correct deeper trigeminal nociceptive pain caused by damage to the trigeminal nerve further along its course. Antidepressive agents with anti-nociceptive properties, anticonvulsants, and anti-inflammatory agents are most commonly used. Newer agents are beginning to replace the commonly used first-line medications. Combination therapy is popular because it maximizes the effect of each drug while reducing the side effects seen in higher-dose monotherapy. Treatment of secondary clinical depression is very important in the management of patients with facial pain, explaining the beneficial dual role of antidepressants in this condition. Alternative and holistic approaches are also popular, but most are not confirmed by controlled studies at the present time.

Recurrent optic neuritis as the presenting manifestation of primary hypereosinophilic syndrome: a report of two cases.

Two patients sustained multiple attacks of optic neuritis with persistent visual loss. An elevated eosinophil count was initially considered an incidental finding. Years later, the diagnosis of primary hypereosinophilic syndrome (HES) was confirmed by skin and bone marrow in one patient and by lung biopsy in the other. Treatment with hydroxyurea in one patient and with continuous low-dose prednisone in the other stopped the optic neuritis attacks, resolved systemic manifestations, and stabilized neurologic manifestations. These cases emphasize that primary HES may be a cause of recurrent optic neuritis, and that delay in diagnosis and treatment of primary HES can lead to visual morbidity.

Pupil-sparing, painless compression of the oculomotor nerve by expanding basilar artery aneurysm: a case of ocular pseudomyasthenia.

BACKGROUND: Oculomotor nerve paresis may have relatively benign but also life-threatening causes. Distinguishing between these is of great clinical importance. OBJECTIVE: To reveal a potential pitfall of the clinical evaluation of oculomotor nerve paresis. PATIENT: Single case observation. RESULTS: A 56-year-old man had fluctuating diplopia and fatigable ptosis, promptly relieved by intravenous edrophonium, leading to the diagnosis of ocular myasthenia gravis. His pupillary function was intact. A few days after the initial diagnosis, he suffered a subarachnoid hemorrhage secondary to the rupture of a basilar artery aneurysm. His ocular symptoms were related to aneurysmal oculomotor nerve compression. CONCLUSION: Patients with oculomotor nerve dysfunction need more detailed evaluation because the underlying cause cannot be safely determined on a clinical basis.

Pathogenesis of the vitreous cloud emanating from subretinal hemorrhage.

OBJECTIVE: To determine the cellular mechanism that allows subretinal hemorrhage to cloud the vitreous. METHODS: We simulated subretinal hemorrhage in a rabbit model by injecting autologous blood beneath the retina. At the first appearance of a cloud in the vitreous a vitrectomy was performed and using a surgical microscope, the retina was searched for breaks. After enucleation and fixation, the retina was searched for microscopic breaks using light and electron microscopy. The vitreous was then examined to determine the character of the cell population in the cloud. In a related study, we sampled and examined the vitreous for its cellular content in patients undergoing vitrectomy to clear cloudy vitreous emanating from subretinal hemorrhage. RESULTS: We found no breaks in the living retina of the animal models or the patients. Microscopic examination of serial sections of the rabbit retina revealed necrosis except for the internal limiting membrane. Fragments of the erythrocytes were seen within the damaged retina and on both sides of the internal limiting membrane. Electron microscopy suggested that the erythrocytic fragments had migrated across the internal limiting membrane. The vitreous cloud in both rabbits and patients contained only fragments of erythrocytes. CONCLUSIONS: Thick subretinal hemorrhage causes necrosis of the overlying retina. Fragments of the erythrocytes infiltrate the retina and cross an intact internal limiting membrane to cloud the vitreous. CLINICAL RELEVANCE: Rapid necrosis of the retina occurs over thick subretinal hemorrhage and indicates the need for early displacement of the hemorrhage from the macula if function is to be preserved and breakthrough prevented.