Hereditary polyneuropathy with optic atrophy due to PDXK variant leading to impaired Vitamin B6 metabolism.

PDXK encodes for a pyridoxal kinase, which converts inactive B6 vitamers to the active cofactor pyridoxal 5'-phosphate (PLP). Recently, biallelic pathogenic variants in PDXK were shown to cause axonal Charcot-Marie-Tooth disease with optic atrophy that responds to PLP supplementation. We present two affected siblings carrying a novel biallelic missense PDXK variant with a similar phenotype with earlier onset. After detection of a novel PDXK variant using Whole Exome Sequencing, we confirmed pathogenicity through in silico protein structure analysis, determination of pyridoxal kinase activity using liquid chromatography-tandem mass spectrometry, and measurement of plasma PLP concentrations using high performance liquid chromatography. Our in silico analysis shows a potential effect on PDXK dimer stability, as well as a putative effect on posttranslational ubiquitination that is predicted to lead to increased protein degradation. We demonstrate that the variant leads to almost complete loss of PDXK enzymatic activity and low PLP levels. Our patients' early diagnosis and prompt PLP replacement restored the PLP plasma levels, enabling long-term monitoring of clinical outcomes. We recommend that patients presenting with similar phenotype should be screened for PDXK mutations, as this is a rare opportunity for treatment.

Potentially blinding adverse drug reaction to peribulbar lignocaine anesthesia: A rare case report.

Peribulbar lignocaine anesthesia is commonly used in ophthalmic surgeries. It rarely causes any severe allergic reaction. A 63-year-old male presented with complicated pseudophakia. He underwent successful vitrectomy under local anesthesia. He later presented with acute-onset proptosis, orbital swelling, and extraocular movement restriction. He was afebrile with normal blood workup and radiological investigations and gave a similar past history. The patient was treated successfully with intravenous medications but two months later developed optic atrophy. An adverse reaction to lignocaine appears to be the most probable cause. Early detection and prompt management of this condition may avert a potentially grave visual outcome. Literature review shows that this case is one of its kinds to report this potentially blinding complication of peribulbar lignocaine anesthesia.

Xanthoma disseminatum with neurological involvement and optic atrophy: improvement with cladribine.

A 9-year-old boy presented with multiple hyperpigmented papules over flexors with polyuria, polydipsia and progressive loss of vision. Histopathology of papule suggested a diagnosis of non-Langerhans cell histiocytosis and systemic evaluation showed central diabetes insipidus and optic atrophy. With a diagnosis of xanthoma disseminatum with significant neurological involvement, he received cladribine therapy and showed significant improvement in both cutaneous and nervous system lesions.

PACAP Attenuates Optic Nerve Crush-Induced Retinal Ganglion Cell Apoptosis Via Activation of the CREB-Bcl-2 Pathway.

Retinal ganglion cell (RGC) apoptosis is considered an important pathological hallmark of glaucoma. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic peptide with potent neuroprotective properties. In our previous study, we found that the expression of PACAP and its high-affinity receptor PACAP receptor type 1 (PAC1R) increased markedly after optic nerve crush (ONC), and occurred mainly in the ganglion cell layer of the retina. This suggests that the upregulation of PACAP may play a vital role in inhibiting RGC death after ONC. Therefore, in the present study, we investigate the specific effects and underlying mechanism of PACAP in RGC death after ONC. Vehicle (physiological saline) or PACAP (1 nM to 200 nM) solution was injected into the vitreous body. Seven days later, the retinas were harvested, and the surviving RGCs were retrogradely labeled with Fluoro-Gold (FG; Fluorochrome) at different concentrations of PACAP. Immunofluorescence double staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay were used to observe the effects of PACAP on RGC apoptosis. Our results showed that PACAP treatment inhibited caspase-3-mediated RGC apoptosis, promoted the phosphorylation of cAMP response element binding protein (CREB), up-regulated the expression of B-cell lymphoma 2 (Bcl-2), and ultimately improved RGC survival. These results suggest that PACAP may prevent RGC apoptosis after ONC via activation of CREB-mediated Bcl-2 transcription. The study thus contributes to a basic understanding of the mechanism by which PACAP decreased RGC apoptosis and provides a theoretical basis for future clinical application of PACAP in the treatment of glaucoma.

Biotinidase deficiency: A treatable cause of opticospinal syndrome in young adults✰.

Diagnosis of biotinidase deficiency is rare and usually made in infancy, through newborn screening or after presenting symptoms. We present the case of 19-year old male with progressive optic atrophy and in a second phase spinal cord syndrome unresponsive to immunosuppressive therapies. After diagnosis of profound biotinidase deficiency, oral biotin substitution was started with partial visual improvement and normalization of gait. This case highlights the possibility of late-onset biotinidase deficiency and its treatable character.

Further characterization of CAPOS/CAOS syndrome with the Glu818Lys mutation in the ATP1A3 gene: A case report.

A 38-year-old female patient experienced recurrent episodes of neurological deterioration during febrile illness at the age of 7 and 8 months, and 2, 4, and 37 years. Acute symptoms comprised unconsciousness, headache, abnormal ocular movements, flaccid paralysis with areflexia, ataxia, dysphagia, and movement disorders. Each episode of neurological deterioration was followed by partial recovery with residual symptoms of progressive disturbance of visual acuity with optic atrophy and hearing loss, moderate intellectual disability, strabismus, ophthalmoplegia, as well as fluctuating degree of gait ataxia, chorea, tremor, and myoclonus. In addition, electrocardiography revealed incomplete right bundle branch block. The genetic testing revealed a de novo heterozygous mutation of c.2452G > A (p.Glu818Lys) in the ATP1A3 gene, which was compatible with the clinical phenotype of CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss)/CAOS syndrome. Here we discuss the significance of clinical features of a patient, overlapping with those of alternating hemiplegia of childhood, along with a literature review.

Refractory Giant Cell Arteritis Complicated by Vision Loss From Optic Atrophy and Maculopathy Associated With Pachymeningitis.

BACKGROUND: We describe a 75-year-old woman who experienced vision loss in her left eye due to biopsy-proven giant cell arteritis (GCA). She subsequently developed pachymeningitis causing refractory headaches and bilateral optic neuropathy and maculopathy. METHODS: Case report with literature review. RESULTS: Eighteen months after the initial diagnosis of GCA, imaging studies in our patient demonstrated pachymeningeal enhancement, and meningeal biopsy confirmed lymphoplasmacytic tissue infiltrates with low frequencies of IgG4+ plasma cells. Laboratory investigation revealed the presence of 3 antiretinal antibodies and antimyeloperoxidase antibodies, consistent with autoimmune retinopathy. Treatment with B-cell-depleting anti-CD20 antibodies suppressed meningeal inflammation and prevented further vision loss. CONCLUSIONS: This case illustrates that bilateral vision loss and chronic headaches in patients with GCA may result from retina-directed autoimmunity and pachymeningitis.

GLP-1-RA Corrects Mitochondrial Labile Iron Accumulation and Improves ß-Cell Function in Type 2 Wolfram Syndrome.

CONTEXT: Type 2 Wolfram syndrome (T2-WFS) is a neuronal and ß-cell degenerative disorder caused by mutations in the CISD2 gene. The mechanisms underlying ß-cell dysfunction in T2-WFS are not known, and treatments that effectively improve diabetes in this context are lacking. OBJECTIVE: Unraveling the mechanisms of ß-cell dysfunction in T2-WFS and the effects of treatment with GLP-1 receptor agonist (GLP-1-RA). DESIGN AND SETTING: A case report and in vitro mechanistic studies. PATIENT AND METHODS: We treated an insulin-dependent T2-WFS patient with the GLP-1-RA exenatide for 9 weeks. An iv glucose/glucagon/arginine stimulation test was performed off-drug before and after intervention. We generated a cellular model of T2-WFS by shRNA knockdown of CISD2 (nutrient-deprivation autophagy factor-1 [NAF-1]) in rat insulinoma cells and studied the mechanisms of ß-cell dysfunction and the effects of GLP-1-RA. RESULTS: Treatment with exenatide resulted in a 70% reduction in daily insulin dose with improved glycemic control, as well as an off-drug 7-fold increase in maximal insulin secretion. NAF-1 repression in INS-1 cells decreased insulin content and glucose-stimulated insulin secretion, while maintaining the response to cAMP, and enhanced the accumulation of labile iron and reactive oxygen species in mitochondria. Remarkably, treatment with GLP-1-RA and/or the iron chelator deferiprone reversed these defects. CONCLUSION: NAF-1 deficiency leads to mitochondrial labile iron accumulation and oxidative stress, which may contribute to ß-cell dysfunction in T2-WFS. Treatment with GLP-1-RA and/or iron chelation improves mitochondrial function and restores ß-cell function. Treatment with GLP-1-RA, probably aided by iron chelation, should be considered in WFS and other forms of diabetes associated with iron dysregulation.

[Memantine for optic nerve atrophy in Friedreich's Ataxia]. / Memantin bei Optikusatrophie in Friedreich-Ataxie.

A 24-year-old patient with Friedreich's ataxia presented with advanced visual loss due to optic nerve atrophy. After interdisciplinary consultation and after obtaining informed consent, an off-label therapy with the N-methyl-D-aspartate (NMDA) antagonist memantine was initiated. In a 1-year follow-up no further loss of the nerve fiber layer could be detected by optical coherence tomography (OCT) and visual acuity remained stable. Despite the limitations of this single and time limited case observational study, memantine should be discussed as an option for treatment of acute optic nerve atrophy in Friedreich's ataxia.

A 43-year-old woman presenting with subacute, bilateral, sequential facial nerve palsies, then developing pseudotumour cerebri.

A patient presented elsewhere with what appeared to be a simple, unilateral, chronic suppurative otitis media and then developed an ipsilateral facial palsy. She soon developed the same problem on the other side. At the time, a brain MRI had been ordered but the clinician did not review it with a radiologist. The surgical specimens were not sent for histopathology. When transferred to our institution 3 months later, the patient had severe bilateral papilloedema due to intracranial hypertension due to missed cerebral venous sinus thrombosis. Further surgery revealed that the pathology in the temporal bone was B-cell lymphoma, which, fortunately, responded to chemoradiotherapy. There was good resolution of the facial palsies, but the patient has severe permanent visual loss due to optic atrophy.

Randomized, double-blind, placebo-controlled study of zeaxanthin and visual function in patients with atrophic age-related macular degeneration: the Zeaxanthin and Visual Function Study (ZVF) FDA IND #78, 973.

BACKGROUND: The purpose of this study is to evaluate whether dietary supplementation with the carotenoid zeaxanthin (Zx) raises macula pigment optical density (MPOD) and has unique visual benefits for patients with early atrophic macular degeneration having visual symptoms but lower-risk National Institute of Health/National Eye Institute/Age-Related Eye Disease Study characteristics. METHODS: This was a 1-year, n = 60 (57 men, 3 women), 4-visit, intention-to-treat, prospective, randomized controlled clinical trial of patients (74.9 years, standard deviation [SD] 10) with mild-to-moderate age-related macular degeneration (AMD) randomly assigned to 1 of 2 dietary supplement carotenoid pigment intervention groups: 8 mg Zx (n = 25) and 8 mg Zx plus 9 mg lutein (L) (n = 25) or 9 mg L ("Faux Placebo," control group, n = 10). Analysis was by Bartlett's test for equal variance, 3-way repeated factors analysis of variance, independent t test (P < 0.05) for variance and between/within group differences, and post-hoc Scheffé's tests. Estimated foveal heterochromic flicker photometry, 1° macular pigment optical density (MPOD QuantifEye(®)), low- and high-contrast visual acuity, foveal shape discrimination (Retina Foundation of the Southwest), 10° yellow kinetic visual fields (KVF), glare recovery, contrast sensitivity function (CSF), and 6° blue cone ChromaTest(®) color thresholds were obtained serially at 4, 8, and 12 months. RESULTS: Ninety percent of subjects completed ≥ 2 visits with an initial Age-Related Eye Disease Study report #18 retinopathy score of 1.4 (1.0 SD)/4.0 and pill intake compliance of 96% with no adverse effects. There were no intergroup differences in 3 major AMD risk factors: age, smoking, and body mass index as well as disease duration and Visual Function Questionnaire 25 composite score differences. Randomization resulted in equal MPOD variance and MPOD increasing in each of the 3 groups from 0.33 density units (du) (0.17 SD) baseline to 0.51 du (0.18 SD) at 12 m, (P = 0.03), but no between-group differences (Analysis of Variance; P = 0.47). In the Zx group, detailed high-contrast visual acuity improved by 1.5 lines, Retina Foundation of the Southwest shape discrimination sharpened from 0.97 to 0.57 (P = 0.06, 1-tail), and a larger percentage of Zx patients experienced clearing of their KVF central scotomas (P = 0.057). The "Faux Placebo" L group was superior in terms of low-contrast visual acuity, CSF, and glare recovery, whereas Zx showed a trend toward significance. CONCLUSION: In older male patients with AMD, Zx-induced foveal MPOD elevation mirrored that of L and provided complementary distinct visual benefits by improving foveal cone-based visual parameters, whereas L enhanced those parameters associated with gross detailed rod-based vision, with considerable overlap between the 2 carotenoids. The equally dosed (atypical dietary ratio) Zx plus L group fared worse in terms of raising MPOD, presumably because of duodenal, hepatic-lipoprotein or retinal carotenoid competition. These results make biological sense based on retinal distribution and Zx foveal predominance.

[Neuropeptides in the treatment of optic nerve atrophy in children].

The study aimed at investigating the therapeutic effect of the cerebrolysin on partial optic nerve atrophy in children. Six hundreds and forty-six children aged from 8 weeks to 18 years have been studied. Cerebrolysin was injected intramuscularly in dose 0,1 ml per 1 kg of body mass daily and retrobulbar in dose 0,3-0,5 ml; an irrigation system was used to treat a posterior segment of the eye. The illness duration was 10-15 days. The positive effect of the drug, in particular with the following optic nerve stimulation, has been shown. Peculiarities of action of cerebrolysin depending on the initial vision acuity and etiology of disease are emphasized.

[Ophthalmological symptoms as key findings in neurosyphilis--diagnosis and therapy]. / Ophthalmologische Symptomatik als Schlüsselbefund der Neurosyphilis--Diagnose und Therapie.

BACKGROUND: The incidence of neurosyphilis, one of the late manifestations of syphilis, is reemerging. Affection of the eye is often associated with the disease. It may present with various clinical symptoms, leading to diagnostic difficulties. In cases of early diagnosis and adequate treatment the prognosis of the disease is good. PURPOSE: The purposes of this study are 1. to analyse clinical manifestations of patients with neurosyphilis on ophthalmological symptoms and 2. to demonstrate the course of the disease and the visual outcome in patients with optic nerve affection in neurosyphilis treated with standard therapy (penicillin G) or adjunct steroids. METHODS: We performed 1. a retrospective analysis of all 23 patients who were treated for neurosyphilis between 2000-2008 at this centre and 2. evaluated a case series of 4 patients with optic nerve affection in neurosyphilis who were treated with penicillin and adjunct methylprednisolone. RESULTS: 91% of the patients with neurosyphilis showed ocular affection in various presentations. The optic nerve was affected in 78%. In 43% ocular symptoms were the exclusive sign of the neurosyphilis. In all patients who were treated with penicillin, visual acuity improved. Adjunct treatment with methylprednisolone resulted in complete visual recovery in two cases. CONCLUSION: Ocular symptoms serve as the key diagnostic findings in neurosyphilis. Treatment of choice is penicillin G. Adjunct treatment with methylprednisolone may improve the visual outcome in patients with optic nerve involvement.