Optic Nerve Degeneration and Reduced Contrast Sensitivity Due to Folic Acid Deficiency: A Behavioral and Electrophysiological Study in Rhesus Monkeys.

Purpose: The purpose of the research was to elucidate the role of folic acid (B9) deficiency in the development of nutritional optic neuritis and to characterize the neurophysiological consequences of optic nerve degeneration in the cortical visual system. Methods: A combined behavioral and electrophysiological approach was applied to study luminance contrast sensitivity in two macaque monkeys affected by nutritional optic neuritis and in two healthy monkeys for comparison. For one monkey, a follow-up approach was applied to compare visual performance before onset of optic neuropathy, during the disease, and after treatment. Results: Optic nerve degeneration developed as a consequence of insufficient dietary intake of folic acid in two exemplars of macaque monkeys. The degeneration resulted in markedly reduced luminance contrast sensitivity as assessed behaviorally. In one monkey, we also measured visual activity in response to varying contrast at the level of single neurons in the cortical visual system and found a striking reduction in contrast sensitivity, as well as a marked increase in the latency of neuronal responses. Prolonged daily folate supplementation resulted in a significant recovery of function. Conclusions: Folic acid deficiency per se can lead to the development of optic nerve degeneration in otherwise healthy adult animals. The optic nerve degeneration strongly affects contrast sensitivity and leads to a distinct reduction in the strength and velocity of the incoming signal to cortical visual areas of the macaque brain, without directly affecting excitability and functional properties of cortical neurons.

Further Evidence on Efficacy of Diet Supplementation with Fatty Acids in Ocular Pathologies: Insights from the EAE Model of Optic Neuritis.

In the experimental autoimmune encephalomyelitis (EAE) mouse model of optic neuritis, we recently demonstrated that diet supplementation with a balanced mixture of fatty acids (FAs), including omega 3 and omega 6, efficiently limited inflammatory events in the retina and prevented retinal ganglion cell (RGC) death, although mechanisms underlying the efficacy of FAs were to be elucidated. Whether FAs effectiveness was accompanied by efficient rescue of demyelinating events in the optic nerve was also unresolved. Finally, the possibility that RGC rescue might result in ameliorated visual performance remained to be investigated. Here, the EAE model of optic neuritis was used to investigate mechanisms underlying the anti-inflammatory effects of FAs, including their potential efficacy on macrophage polarization. In addition, we determined how FAs-induced rescue of RGC degeneration was related to optic nerve histopathology by performing ultrastructural morphometric analysis with transmission electron microscopy. Finally, RGC rescue was correlated with visual performance by recording photopic electroretinogram, an efficient methodology to unravel the role of RGCs in the generation of electroretinographic waves. We conclude that the ameliorative effects of FAs were dependent on a predominant anti-inflammatory action including a role on promoting the shift of macrophages from the inflammatory M1 phenotype towards the anti-inflammatory M2 phenotype. This would finally result in restored optic nerve histopathology and ameliorated visual performance. These findings can now offer new perspectives for implementing our knowledge on the effectiveness of diet supplementation in counteracting optic neuritis and suggest the importance of FAs as possible adjuvants in therapies against inflammatory diseases of the eye.

MD1003 (High-Dose Pharmaceutical-Grade Biotin) for the Treatment of Chronic Visual Loss Related to Optic Neuritis in Multiple Sclerosis: A Randomized, Double-Blind, Placebo-Controlled Study.

BACKGROUND: Chronic visual loss is a disabling feature in patients with multiple sclerosis (MS). It was recently shown that MD1003 (high-dose pharmaceutical-grade biotin or hdPB) may improve disability in patients with progressive MS. OBJECTIVE: The aim of this study was to evaluate whether MD1003 improves vision compared with placebo in MS patients with chronic visual loss. METHODS: The MS-ON was a 6-month, randomized, double-blind, placebo-controlled study with a 6-month open-label extension phase. Adult patients with MS-related chronic visual loss of at least one eye [visual acuity (VA) below 0.5 decimal chart] were randomized 2:1 to oral MD1003 300 mg/day or placebo. The selected eye had to show worsening of VA within the past 3 years following either acute optic neuritis (AON) or slowly progressive optic neuropathy (PON). The primary endpoint was the mean change from baseline to month 6 in VA measured in logarithm of the minimum angle of resolution (logMAR) at 100% contrast of the selected eye. Visually evoked potentials, visual field, retinal nerve fiber layer (RNFL) thickness, and health outcomes were also assessed. RESULTS: Ninety-three patients received MD1003 (n = 65) or placebo (n = 28). The study did not meet its primary endpoint, as the mean change in the primary endpoint was nonsignificantly larger (p = 0.66) with MD1003 (- 0.061 logMAR, + 3.1 letters) than with placebo (- 0.036 logMAR, + 1.8 letters). Pre-planned subgroup analyses showed that 100% contrast VA improved by a mean of + 2.8 letters (- 0.058 logMAR) with MD1003 and worsened by - 1.5 letters (+ 0.029 logMAR) with placebo (p = 0.45) in the subgroup of patients with PON. MD1003-treated patients also had nonsignificant improvement in logMAR at 5% contrast and in RNFL thickness and health outcome scores when compared with placebo-treated patients. There was no superiority of MD1003 vs placebo in patients with AON. The safety profile of MD1003 was similar to that of placebo. CONCLUSIONS: MD1003 did not significantly improve VA compared with placebo in patients with MS experiencing chronic visual loss. An interesting trend favoring MD1003 was observed in the subgroup of patients with PON. Treatment was overall well tolerated. TRIAL REGISTRATION: EudraCT identifier 2013-002112-27. ClinicalTrials.gov Identifier: NCT02220244 FUNDING: MedDay Pharmaceuticals.

Case-centered Analysis of Optic Neuritis After Vaccines.

We evaluated the risk of optic neuritis (ON) after vaccines, using a case-centered analysis, comparing the time since vaccination for the patients with ON with that for all similar vaccinees in a large integrated health plan population. We did not detect any association between ON and receipt of any type of vaccine.

The difficulties with vitamin B12.

A 22-year-old woman presented with progressive sensory ataxia and optic neuropathy. Previous investigation by her general practitioner had found a low serum vitamin B12, which had been corrected with oral supplementation. Neurological investigations showed raised plasma homocysteine and methylmalonic acid towards the upper limit of normal with a low serum vitamin B12 MRI showed an extensive cord lesion in keeping with subacute combined degeneration of the spinal cord. We treated her with high dose parenteral vitamin B12 and she has made a partial recovery. We discuss the management of patients who present with neurological manifestations of vitamin B12 deficiency; highlighting the fact that parenteral replacement is needed in such cases, even if the serum vitamin B12 level appears to be normal. We also discuss ancillary investigations that should be performed in patients with suspected vitamin B12 deficiency.

Normal levels of cerebrospinal fluid hypocretin-1 and daytime sleepiness during attacks of relapsing-remitting multiple sclerosis and monosymptomatic optic neuritis.

There is emerging evidence that multiple sclerosis (MS), the hypothalamic sleep-wake regulating neuropeptide hypocretin-1 (hcrt-1) and the sleep disorder narcolepsy may be connected. Thus, the major pathophysiological component of narcolepsy is lack of hcrt-1. Dysfunction of the hypocretin system has been reported in MS case reports with attacks of hypothalamic lesions, undetectable cerebrospinal fluid (CSF) hcrt-1 and hypersomnia, but not found during remission in small samples. Finally, daytime sleepiness, the major symptom of narcolepsy, is reported in several MS populations, and there are case reports of co-existent narcolepsy and MS. However, it is unknown whether hcrt-1 and daytime sleepiness generally change during MS attacks. We therefore analyzed whether daytime sleepiness (using the Epworth Sleepiness Scale (ESS)) and CSF hcrt-1 levels differed between MS attack and remission, in 48 consecutively referred patients with relapsing-remitting MS (RRMS) or monosymptomatic optic neuritis (MON). Twenty-seven patients were in attack and 21 in remission. ESS was normal both during attacks (5.4 +/- 3.0) and remission (5.8 +/- 2.6), and mean CSF hcrt-1 was normal (456 +/- 41 pg/ml). No statistically significant differences were found between attack and remission. MRI scans revealed no hypothalamic lesions. The results show that the hypocretin system is intact and sleepiness is not typical in RRMS and MON without hypothalamic lesions on MRI.

Homeopathy in Cuban epidemic neuropathy: an open clinical trial.

In an outbreak of epidemic neuropathy (EN) in Cuba (1992-1993), most patients were improved by vitamin therapy. In subjects with residual symptoms, alternative treatments including homeopathy were suggested to ameliorate optic and peripheral signs of the disease. An open clinical pilot trial was conducted on 31 patients with long standing symptoms of optic (OPTI group, n=15) or peripheral EN (PERI group, n=16). During the trial, OPTI and PERI patients continued the same treatment that they received before. Carboneum sulphuratum and Tabacum in homeopathic dilutions were administered for 30 days. These medicines are specific to optic EN, but not closely linked with peripheral EN. Clinical status was evaluated by neurological and ophthalmologic tests at diagnosis (Ddiag), 7 days before homeopathic treatment (D0) and 90 days after (D90). From D0 to D90, the percentages of improvement were 73.3% for the OPTI form and 12.5% for the PERI form. The percentage of improved OPTI patients was significantly higher after the homeopathic treatment vs the period between Ddiag and D0 for optical EN (P<0.01), but not for PERI subjects (P>0.05). In the OPTI group, colour vision, visual acuity and visual field improved after homeopathic treatment (P<0.001), these parameters did not change between Ddiag and D90 (P>0.05). Carboneum sulphuratum and Tabacum showed a reasonable effectiveness in optical EN, but were not effective in PERI EN.

[An early-onset case of acute disseminated encephalomyelitis with bilateral thalamic lesions on MRI].

We report the case of 5-year-old girl with acute disseminated encephalomyelitis (ADEM), whose MRI showed bilateral thalamic lesions. She suffered from left optic neuritis and generalized convulsion. Examination of cerebrospinal fluid revealed elevation of mononuclear cells and myelin basic protein (MBP). MRI showed the swelling of left optic nerve and high intensity areas of bilateral thalamus. After methylprednisolone pulse therapy, her visual acuity was dramatically improved and bilateral thalamic lesions were decreased. In childhood, bilateral thalamic lesions were observed in several diseases, such as viral encephalitis. Reye syndrome, Leigh syndrome and acute necrotizing encephalopathy. Demyelinating diseases involving the grey matter were very rare, but we must consider the presence of symmetrical thalamic involvement in patients with ADEM.

Unusual combination of night blindness and optic neuropathy after biliopancreatic bypass.

Night blindness and optic neuropathy were the presenting symptoms of an iatrogenic malabsorption syndrome in a 64-year old female. This case illustrates the necessity of lifelong vitamin supplementation after biliopancreatic bypass for morbid obesity.

Disruption of the blood-brain barrier in experimental optic neuritis: immunocytochemical co-localization of H2O2 and extravasated serum albumin.

PURPOSE: To probe the role of endogenous hydrogen peroxide (H2O2) in the pathogenesis of disruption of the blood-brain barrier (BBB) associated with experimental allergic encephalomyelitis (EAE), an animal model for primary central nervous system demyelination. METHODS: Strain-13 guinea pigs were sensitized for EAE with central myelin in complete Freund's adjuvant. Magnetic resonance imaging with Gd-DTPA was performed twice a week for 2 weeks to assess disruption of the BBB, in vivo, by the enhancement of the optic nerves. Two weeks after antigenic sensitization, ultracytochemical localization of endogenous H2O2 was performed using the cerium perhydroxide method, with co-localization of endogenous serum albumin extravasation using gold-labeled antibodies against serum albumin. Examination of blood vessels for perivascular immunogold-labeled serum albumin and H2O2 derived reaction product began in the optic nerve head and proceeded toward the retrobulbar optic nerve until a total of 20 vessels were evaluated per animal. RESULTS: Magnetic resonance imaging revealed Gd-DTPA enhancement of the optic nerves in all animals sensitized for EAE. Optic nerve ultrastructure revealed colloidal gold-labeled antibodies against serum albumin in the perivascular and adjacent interstitial spaces of capillaries and small venules in which H2O2 derived cerium perhydroxide reaction product was also simultaneously evident. Immunogold-labeled serum albumin was predominantly confined to the intravascular compartment of the optic nerve in the absence of perivascular H2O2 and/or perivascular foci of inflammatory cells. The difference between the mean percentage of blood vessels (61.8%) with co-localization of perivascular immunogold-labeled serum albumin and cerium perhydroxide reaction product, to the mean percentage of blood vessels (9.5%) with perivascular immunogold-labeled serum albumin in the absence of cerium perhydroxide, was statistically significant (P = 0.0019). CONCLUSIONS: Endogenous H2O2, found at the foci of BBB disruption, may be one of the mediators involved in the alteration of vascular permeability in experimental optic neuritis.

Uncommon chiasmal lesions: demyelinating disease, vasculitis, and cobalamin deficiency.

We report on eight patients who presented for evaluation of unexplained visual loss. They all showed a typical chiasmal visual field defect (bitemporal hemianopia, junction scotoma). In all patients, high-resolution computer-assisted tomographic (CT) scans of the sellar region were normal, and neither the medical history nor additional ophthalmological findings pointed to any explanation for the underlying disease. Six patients seemed to have suffered from chiasmal optic neuritis. Magnetic resonance imaging (MRI) scans could elucidate the diagnosis in five cases: white-matter lesions typical of multiple sclerosis (MS) were found and, additionally, in four cases an enlargement of the chiasm or barrier defect was revealed in post-gadolinium MRI. In one patient, MRI was normal. He recovered completely after megadose steroid therapy. One patient developed motoric symptoms of MS during the following year, another patient had mild sensory symptoms and recurrence of severe optic neuritis. An MR-proven chiasmal lesion due to a leukocytoclastic immunovasculitis combined with small subcortical white-matter lesions was diagnosed in another patient. The field defects disappeared spontaneously. In a 28-year-old woman a low vitamin B12 level was found in routine blood samples. Parenteral vitamin B12 substitution led to an almost complete recovery of the visual field defects. Chiasmal optic neuritis may occur isolated or during the course of MS. Megadose steroids may be of value if contraindications have been ruled out. A chiasmal visual field defect caused by vitamin B12 deficiency is very uncommon. A similar case was reported in 1961.

[Early diagnosis and immunocorrective therapy of recurrent facial neuritis as a manifestation of Melkersson-Rosenthal syndrome in adults and children]. / Ranniaia diagnostika i immunokorrigiruiushchaia terapiia retsidivi- ruiushchego nevrita litsevogo nerva kak proiavlenie sindroma Mel'kerssona-Rossolimo-Rozentalia u vzroslykh i detei.

Clinical and immunological examinations of adults and children with Melkersson-Rossolimo-Rosenthal syndrome have revealed immunity deficiency: a decrease of the number of T and B cells, a low immunoglobulin content and the presence of the ++neuro-allergic syndrome according to the increased level of cerebral antibodies. The role of deembiogenetic stigmas in the diagnosis establishment has been demonstrated. The authors suggest the use of immunomodulating therapy including interferogens and immunostimulants of T and B cells (galascorbin and myelopide). Provide evidence for the efficacy of the treatment elaborated.

[Slowly reversible central scotoma: iatrogenic effect of hyperbaric oxygenation in the treatment of multiple sclerosis]. / Le scotome central lentement réversible: un effet iatrogène de l'oxygénothérapie hyperbare dans le traitement de la sclérose en plaques.

Considerable enthusiasm has been raised in the past about the use of Hyperbaric Oxygen (HBO) in various diseases, usually otherwise untreatable. Recently, special attention has been drawn on its hypothetical beneficial effects on multiple sclerosis (MS). We have witnessed a rare, though known, side-effect of HBO on a patient suffering from MS. She developed an acute, bilateral, centro-caecal scotoma, from which she slowly recovered several days after. The forementioned case led us to a review of the literature concerning: Various attempts to employ HBO in ophthalmology Side-effects of oxygen on eye and vision Possible mechanisms of ocular toxicity of oxygen. It appears from this review that we should be extremely cautious about using HBO on MS patients, particularly able to develop such side-effects.

Nutritional effects of zinc on ocular and systemic physiology.

Zinc, an essential mineral in human nutrition, has multiple and complex ocular and systemic functions. Zinc deficiency is characterized by growth retardation, reduced appetite, skin changes, impaired reproductive development, impaired taste acuity, and impaired wound healing. Zinc deficiency may also cause or contribute to learning problems. Observations of Denver children have suggested that suboptimum zinc nutriture may be quite common in otherwise normal infants and children in the United States. The most likely cause of this deficiency is dietary insufficiency. High concentrations of zinc are found in human ocular tissues and are closely related to visual function. When zinc levels are inappropriately low, results can include ocular birth defects, reduced ability to dark adapt, excessively low IOP, and optic neuritis. Correction of zinc deficiency with zinc supplementation must be done cautiously because excessive zinc can interfere with the metabolism of copper and zinc.

Some recent advances in the clinical aspects of multiple sclerosis.

UNLABELLED: Recent work on the clinical aspects of multiple sclerosis is reviewed with particular regard to symptomatology: New approaches to clinical symptoms and the identification of more subtle impairments are illustrated by recent studies of visual function in M.S. patients; pathophysiology: It is now widely appreciated that the dysfunction observed in patients is not determined solely by histologically demonstrable demyelination. The function of the demyelinated neuron is highly variable, being dependent upon factors which may change from day to day. Recent ideas about 'neuro-electric blocking factors' and other factors that may influence demyelinated neurons and hence symptoms are discussed; diagnosis: tests on C.S.F., electro-physiological and psychophysiological tests and computer tomography as aids to diagnosis and the controversy over 'specific' blood tests are reviewed; course and prognosis: Long term follow-up studies confirm that, in a significant proportion of cases, the course of M.S. may be benign and have identified some early prognostic indices; TREATMENT: The results of trials of symptomatic (spinal cord stimulation) and would-be curative therapies (such as dietary supplementation with poly-unsaturated fatty acids and immunosuppression) are briefly discussed.

Cupping of the optic disc in ischemic optic neuropathy.

Stereophotographs of the optic disc were reviewed in 78 patients with ischemic optic neuropathy (ION). Only 10% (6) of 61 nonarteritic (idiopathic) ION eyes developed optic disc cupping similar to that seen in glaucomatous eyes. Five of ten eyes with ION due to giant cell arteritis had cupping simulating glaucoma; however, two had elevated intraocular pressure, and the other three had large physiologic cups in the opposite eye. Optic disc pallor was proportionately more severe in ION eyes than in glaucomatous eyes of similar cup size. While there are similarities in the type of visual field loss in ION and glaucoma, the two disorders differ in the usual appearance of the disc after field loss has occurred and in the portion of the field most frequently affected. These observations suggest that if both disorders have an ischemic mechanism, there is a difference in the nature or distribution of the ischemia. There should be little difficulty under most circumstances in making the clinical differentiation between a disc that has suffered ION and a disc that has suffered pressure-induced damage, although occasional instances of ION may be classified as low-tension glaucoma on the basis of field loss and cupping without elevated intraocular pressure.