Dural Venous Sinus Thrombosis and Papilledema Related to JAK2 Mutation: A Case Series.

BACKGROUND: Dural venous sinus thrombosis (DVST) is an important cause of papilledema. Patients diagnosed with DVST should undergo work-up for underlying hypercoagulable state, including genetic causes. One important prothrombotic mutation is in the JAK2 gene, which is a driver of myeloproliferative neoplasms including polycythemia vera (PV). We aimed to determine the prevalence of JAK2 mutation in patients in presenting to neuro-ophthalmology clinic with DVST and papilledema. METHODS: Retrospective case series of patients seen in a tertiary neuro-ophthalmology practice who presented with papilledema due to DVST and were investigated for presence of JAK2 mutation. RESULTS: Four out of 15 patients with DVST (26%) were found to have JAK2 V617F mutation which led to subsequent diagnosis of PV in 2. One additional patient had a known diagnosis of essential thrombocytosis. We describe the clinical presentation of these four patients with papilledema and JAK2 mutation. CONCLUSIONS: A significant proportion of patients with papilledema secondary to DVST will harbor mutations in the JAK2 gene. Clinicians should be aware of this mutation as early testing will facilitate timely diagnosis and treatment of myeloproliferative disease to improve prognosis and reduce risk of recurrent thrombotic events.

Papilledema from gain-of-function mutations in the STAT3 gene.

BACKGROUND: Signal Transducer and Activator of Transcription 3 (STAT3) gain-of-function germline mutations are associated with diverse clinical manifestations, including autoimmune cytopenia, lymphadenopathy, immunodeficiency, endocrinopathy, and enteropathy. We describe a new feature: raised intracranial pressure with papilledema. MATERIALS AND METHODS: Report of two cases. RESULTS: The first patient had a de novo heterozygous c.2144C>T (p.Pro715Leu) mutation in the STAT3 gene. At age 1 she had papilledema with marked sheathing of the proximal vessels on the optic discs. Follow-up 8 years later showed chronic papilledema, cystoid macular edema, and vision loss. The second patient had a de novo heterozygous c.2147C>T (p.Thr716Met) mutation. At age 12 he developed papilledema, which recurred despite treatment. In both patients, repeated sampling of the cerebrospinal fluid demonstrated a lymphocytic pleocytosis. CONCLUSIONS: Papilledema can occur as a manifestation of STAT3 gain-of-function mutation, sometimes accompanied by prominent vascular sheathing and cystoid macular edema. The mechanism may be chronic meningeal infiltration by white blood cells, impairing cerebrospinal fluid absorption.

Implication of VEGF and aquaporin 4 mediating Müller cell swelling to diabetic retinal edema.

PURPOSE: Aquaporin 4 (AQP4), a water channel protein, is known to be expressed in retinal Müller cells. The purpose of this study was to determine the effects of VEGF and AQP4 channels on the volumetric changes in Müller cells. METHODS: Retinas from diabetic rats and a cultured Müller cell line, TR-MUL5, were used in this study. Intravitreal injections of VEGF or PBS were performed on either streptozotocin (STZ)-induced diabetic or normoglycemic rats. Retinal sections were immunostained for anti-glial fibrillary acidic protein (GFAP), anti-AQP4, and anti-VEGF. VEGF protein levels from collected retinas were determined by western blot analysis. Volumetric changes and nitric oxide (NO) levels in cultured Müller cells were determined using flow cytometry (FACS), in the presence or absence of VEGF and TGN-020, a selective AQP4 inhibitor. RESULTS: In the diabetic rat retina, VEGF immunoreactivity was concentrated in the internal retinal layers, and AQP4 immunoreactivity was higher than controls. The expressions of AQP4 were colocalized with GFAP. Protein levels of VEGF in the hyperglycemic rat retina were significantly higher than controls. FACS analyses showed that exposure to VEGF enlarged Müller cells, while exposure to TGN-020 suppressed the enlargement. Intracellular levels of NO were increased after exposure to VEGF, which was suppressed following the addition of TGN-020. CONCLUSION: The observed Müller cell swelling is mediated by VEGF and AQP4.

Sox7, Sox17, and Sox18 Cooperatively Regulate Vascular Development in the Mouse Retina.

Vascular development and maintenance are controlled by a complex transcriptional program, which integrates both extracellular and intracellular signals in endothelial cells. Here we study the roles of three closely related SoxF family transcription factors-Sox7, Sox17, and Sox18 -in the developing and mature mouse vasculature using targeted gene deletion on a mixed C57/129/CD1 genetic background. In the retinal vasculature, each SoxF gene exhibits a distinctive pattern of expression in different classes of blood vessels. On a mixed genetic background, vascular endothelial-specific deletion of individual SoxF genes has little or no effect on vascular architecture or differentiation, a result that can be explained by overlapping function and by reciprocal regulation of gene expression between Sox7 and Sox17. By contrast, combined deletion of Sox7, Sox17, and Sox18 at the onset of retinal angiogenesis leads to a dense capillary plexus with a nearly complete loss of radial arteries and veins, whereas the presence of a single Sox17 allele largely restores arterial identity, as determined by vascular smooth muscle cell coverage. In the developing retina, expression of all three SoxF genes is reduced in the absence of Norrin/Frizzled4-mediated canonical Wnt signaling, but SoxF gene expression is unaffected by reduced VEGF signaling in response to deletion of Neuropilin1 (Npn1). In adulthood, Sox7, Sox17, and Sox18 act in a largely redundant manner to maintain blood vessel function, as adult onset vascular endothelial-specific deletion of all three SoxF genes leads to massive edema despite nearly normal vascular architecture. These data reveal critical and partially redundant roles for Sox7, Sox17 and Sox18 in vascular growth, differentiation, and maintenance.

Phenotypic and genotypic characteristics of cryopyrin-associated periodic syndrome: a series of 136 patients from the Eurofever Registry.

OBJECTIVE: To evaluate genetic, demographic and clinical features in patients with cryopyrin-associated periodic syndrome (CAPS) from the Eurofever Registry, with a focus on genotype-phenotype correlations and predictive disease severity markers. METHODS: A web-based registry retrospectively collected data on patients with CAPS. Experts in the disease independently validated all cases. Patients carrying NLRP3 variants and germline-mutation-negative patients were included. RESULTS: 136 patients were analysed. The median age at disease onset was 9 months, and the median duration of follow-up was 15 years. Skin rash, musculoskeletal involvement and fever were the most prevalent features. Neurological involvement (including severe complications) was noted in 40% and 12% of the patients, respectively, with ophthalmological involvement in 71%, and neurosensory hearing loss in 42%. 133 patients carried a heterozygous, germline mutation, and 3 patients were mutation-negative (despite complete NLRP3 gene screening). Thirty-one different NLRP3 mutations were recorded; 7 accounted for 78% of the patients, whereas 24 rare variants were found in 27 cases. The latter were significantly associated with early disease onset, neurological complications (including severe complications) and severe musculoskeletal involvement. The T348M variant was associated with early disease onset, chronic course and hearing loss. Neurological involvement was less strongly associated with V198M, E311 K and A439 V alleles. Early onset was predictive of severe neurological complications and hearing loss. CONCLUSIONS: Patients carrying rare NLRP3 variants are at risk of severe CAPS; onset before the age of 6 months is associated with more severe neurological involvement and hearing loss. These findings may have an impact on treatment decisions.

The cysteinyl leukotriene 2 receptor mediates retinal edema and pathological neovascularization in a murine model of oxygen-induced retinopathy.

Leukotrienes have been implicated in the pathogenesis of degenerative diabetic retinopathy, with research focusing primarily on leukotriene B(4), with little attention devoted to the cysteinyl leukotrienes (cysLTs), which act through cysLT receptors (CysLT(1)R and CysLT(2)R). We demonstrate here the presence of CysLT(2)R in pericytes and endothelial cells of superficial retinal vasculature using an indirect assay by assessment of ß-galactosidase expression in CysLT(2)R-knockout (KO) mice. Retinal damage was induced in KO and wild-type (WT) mice using an established oxygen-induced retinopathy (OIR) model. CysLT(2)R expression following OIR was intensely up-regulated compared to sham-treated controls. Staining with Griffonia simplicifolia lectin revealed enhanced tissue damage (as assessed by vasoobliteration/vasoproliferation) in KO mice compared to WT controls, yet the opposite was true with respect to retinal edema. However, vascular endothelial growth factor receptor 1 (VEGFR1) transcripts were increased by OIR similarly with respect to genotype. Intravitreal application of exogenous cysLTs elicited greater vasculature leakage (assessed ex vivo) in eyes from WT mice compared to KO mice. While mRNA encoding enzymes for various components of the leukotriene cascade were detected in sham- and OIR-treated retinas, only prostaglandins and hydroxyeicosatetraenoic acids, but not leukotrienes, were detected in A23187-treated retina preparations. Together, these results implicate the CysLT(2)R in the progression of ischemic retinopathy.

Selective over-expression of endothelin-1 in endothelial cells exacerbates inner retinal edema and neuronal death in ischemic retina.

The level of endothelin-1 (ET-1), a potent vasoconstrictor, was associated with retinopathy under ischemia. The effects of endothelial endothelin-1 (ET-1) over-expression in a transgenic mouse model using Tie-1 promoter (TET-1 mice) on pathophysiological changes of retinal ischemia were investigated by intraluminal insertion of a microfilament up to middle cerebral artery (MCA) to transiently block the ophthalmic artery. Two-hour occlusion and twenty-two-hour reperfusion were performed in homozygous (Hm) TET-1 mice and their non-transgenic (NTg) littermates. Presence of pyknotic nuclei in ganglion cell layer (GCL) was investigated in paraffin sections of ipsilateral (ischemic) and contralateral (non-ischemic) retinae, followed by measurement of the thickness of inner retinal layer. Moreover, immunocytochemistry of glial fibrillary acidic protein (GFAP), glutamine synthetase (GS) and aquaporin-4 (AQP4) peptides on retinal sections were performed to study glial cell reactivity, glutamate metabolism and water accumulation, respectively after retinal ischemia. Similar morphology was observed in the contralateral retinae of NTg and Hm TET-1 mice, whereas ipsilateral retina of NTg mice showed slight structural and cellular changes compared with the corresponding contralateral retina. Ipsilateral retinae of Hm TET-1 mice showed more significant changes when compared with ipsilateral retina of NTg mice, including more prominent cell death in GCL characterized by the presence of pyknotic nuclei, elevated GS immunoreactivity in Müller cell bodies and processes, increased AQP-4 immunoreactivity in Müller cell processes, and increased inner retinal thickness. Thus, over-expression of endothelial ET-1 in TET-1 mice may contribute to increased glutamate-induced neurotoxicity on neuronal cells and water accumulation in inner retina leading to edema.

Familial idiopathic intracranial hypertension with variable phenotype.

Familial occurrence of Idiopathic intracranial hypertension has been rarely reported in the literature. Idiopathic intracranial hypertension, both with and without papilloedema is only described in two families before, though one had a probable diagnosis. We report a family of mother and her two daughters. A 37 year old woman was diagnosed with idiopathic intracranial hypertension. Her 7 year old, younger daughter presented a year later with similar symptoms. She did not respond to medical treatment and required Lumbo-peritoneal shunt, Ventriculo-peritoneal shunt and bilateral sub-temporal decompression. Her elder daughter later presented with headaches and idiopathic intracranial hypertension without papilloedema was diagnosed at the age of 13 years. Further insight into the patterns of inheritance is required and other family members should be offered screening, even if papilloedema is not present.

Is idiopathic intracranial hypertension without papilledema a risk factor for migraine progression?

The association of chronic migraine (CM) with an idiopathic intracranial hypertension without papilledema (IIHWOP), although much more prevalent than expected in clinical series of CM sufferers, is not included among the risk factors for migraine progression. We discuss the available evidence supporting the existence of a pathogenetic link between CM and idiopathic intracranial hypertensive disorders and suggest a causative role for IIHWOP in migraine progression.

Clinical and radiographic findings in two brothers affected with a novel mutation in matrix metalloproteinase 2 gene.

The two well-described osteolysis syndromes associated with matrix metalloproteinase-2 deficiency and mutations in the metalloproteinase-2 gene are Torg-Winchester syndrome and nodulosis-arthropathy-osteolysis variant. They are characterized by carpal-tarsal destruction, subcutaneous nodules, and generalized osteoporosis and show autosomal recessive inheritance. Herein, we report two siblings affected with a novel mutation in matrix metalloproteinase 2 gene and discuss their clinical and radiographic findings.

Pseudotumor cerebri from sinus venous thrombosis, associated with polycystic ovary syndrome and hereditary hypercoagulability.

OBJECTIVE: The association of pseudotumor cerebri, visual impairment, hypothyroidism, polycystic ovary syndrome (PCOS), and a hypercoagulable state due to a factor V and a prothrombin mutation has not been reported previously. CASE REPORT: A 20-year-old obese woman developed menstrual cycle irregularities since age 14 years, initially bitemporal and latter diffuse headache since age 14 years, and bilateral visual impairment, described as sparkling black points. Ophthalmologically there was a recurrent papilledema. Clinical neurologic investigations revealed sore neck muscles and hirsutism. Magnetic resonance imaging of the brain, orbita and cervical spine, and investigations of cerebrospinal fluid were non-informative. Visually evoked potentials revealed demyelination of the optic nerves. Gynecologic investigations revealed PCOS and endocrinologic investigations hypothyroidism and hyperandrogenism. Tests for thrombophilia disclosed a heterozygote state for the G1.697A factor V Leiden and the G20.210A prothrombin mutation. A possible relationship between pseudotumor cerebri and the ophthalmologic, gynecologic, endocrinologic and coagulation abnormalities is discussed. CONCLUSIONS: For the first time we describe the association of pseudotumor cerebri, optic nerve demyelination, PCOS, other endocrinologic abnormalities, and thrombophilia due to a factor V and prothrombin mutation. A causal relationship between these abnormalities remains elusive.

Familial idiopathic intracranial hypertension.

AIM: To analyze the development and occurrence of the idiopathic intracranial hypertension and consequent visual loss in a family affected with idiopathic intracranial hypertension. METHODS: We studied 15 members of the same family and found six of them affected with idiopathic intracranial hypertension, which was accompanied with visual loss as a repercussion of the disease. Idiopathic intracranial hypertension was diagnosed on neurological and radiological examination. Visual examination to establish visual loss included fundoscopy, visual acuity, visual field testing, and ultrasonography of the optic nerve. RESULTS: The construction of a family tree and detailed examination of 15 family members revealed idiopathic intracranial hypertension with visual disturbances, even amaurosis, and different stages of visual field constriction in three members of the family: the mother and her two daughters. Due to the symptoms of idiopathic intracranial hypertension, such as headaches, nausea, vertigo, and the presence of transient visual obscuration and papilledema, in three other members of this family (aged 16, 17, and 25 years), we considered a presumptive diagnosis of idiopathic intracranial hypertension, and the need for thorough follow-up. Medical data on the family grandmother, who died 34 years ago, suggested that she also had symptoms of idiopathic intracranial hypertension. One of the patients underwent surgical treatment by a lumbo-peritoneal shunt operation worsening of the symptoms. CONCLUSION: It is very important to include idiopathic intracranial hypertension in differential diagnosis of papilledema and recognize it in early stages to prevent vision loss. Current successful therapeutic approaches and close follow-up of such patients require teamwork of neurologists, ophthalmologists, and neurosurgeons.

Acro-oto-ocular syndrome: further evidence for a new autosomal recessive disorder.

We report on a patient born to consanguineous parents and presenting with pseudopapilledema, mixed hearing loss, and minor facial and limb anomalies. To our knowledge, there is just one similar description of this syndrome in three members of a Brazilian kindred whose parents were also consanguineous, suggesting autosomal recessive inheritance. We compare the findings of our patient with these previous reported cases and discuss the differential diagnoses of this new syndrome, which we suggest be named the acro-oto-ocular syndrome.

Autosomal dominant retinitis pigmentosa and Coats'-like disease.

Two patients with retinitis pigmentosa of the dominant type and a Coats'-like syndrome were studied. The aetiology of the Coats'-like syndrome in retinitis pigmentosa is obscure. The principal theories will be reported in this paper. The association between retinitis pigmentosa and Coats'-like disease has been reported many times in a sporadic way (Zamorani, 1956; Morgan and Crawford, 1968). As far as we know this association in more than one member of the same pedigree has been published only in two papers (Schmidt and Faulborn, 1972; Lanier, McCrary and Justice, 1976). Below we describe the case of two brothers suffering from retinitis pigmentosa of the dominant type and Coats'-like syndrome. To our knowledge this is the first report in English of the occurrence in a family of association of retinitis pigmentosa of the dominant type and Coats'-like syndrome which occurred in two brothers of non consanguineous parents.

Genetic and ultrasound study of abnormalities of the optic nerve head.

The authors, after reviewing the literature, particularly the classification of optic nerve-head abnormalities, describe several clinical cases dealing especially with the notable diagnostic possibilities of ultrasound examination.

[Familial binasal visual field contraction]. / Familäre binasale Gesichtsfeldkontraktion.

A 45-year-old heavy smoker was referred to the clinic for acute unilateral visual acuity reduction and irregular visual field constriction. An ischemic optic neuropathy with ipsilateral pit of the disc and medullated parapapillar nerve fibres was diagnosed. In spite of a normal fundus a visual field contraction in the upper nasal quadrant was found on the other eye. The son of the patient had bilateral crater-like holes of the disc with binasal visual field contraction. Similar visual field defects were found in the patient's daughter, with pseudopapilledema.