Orbital infantile haemangioma: radiological features and treatment - case series and literature review.

AIM: The aim of this study is to report a retrospective case series on orbital infantile haemangiomas (OIH). Radiological features and treatment with oral propranolol (OP) are illustrated along with an updated literature review. METHODS: A retrospective chart review of six children, diagnosed with OIH from November 2015 to October 2016, was carried out. Only children with deep documented orbital involvement were included. All patients underwent magnetic resonance imaging (MRI) under general anaesthesia. OP was administered to the infants according to the Nottingham Children's Hospital guideline. As per the guideline, a preliminary paediatric assessment was performed and a 1 mg/kg test dose was administered, followed by definitive treatment at a dosage of 2 mg/kg in three divided doses. RESULTS: Average age at presentation was within the first 3 weeks of life. T1 hypointensity, T2 hyperintensity, avid enhancement with contrast, and the presence of flow-voids appear a fixed pattern of OIH on MRI. Response to treatment was noticed within 4 weeks in all children, and two of them (33.3%) responded within the first 7 days. In two children (33.3%), the haemangioma became clinically undetectable by the seventh month of treatment, while the other four (66.6%) experienced an almost complete regression of the OIH by the last follow-up. No complications were found. CONCLUSIONS: Our series strengthens the understanding that MRI is the preferred imaging modality in the investigation of OIH, showing vascular features, detailed orbital extension, and possible associated malformations. OP is the treatment of choice for OIH, and our study confirms its safety and effectiveness.

Abnormal retinal development associated with FRMD7 mutations.

Idiopathic infantile nystagmus (IIN) is a genetically heterogeneous disorder, often associated with FRMD7 mutations. As the appearance of the retina is reported to be normal based on conventional fundus photography, IIN is postulated to arise from abnormal cortical development. To determine whether the afferent visual system is involved in FRMD7 mutations, we performed in situ hybridization studies in human embryonic and fetal stages (35 days post-ovulation to 9 weeks post-conception). We show a dynamic retinal expression pattern of FRMD7 during development. We observe expression within the outer neuroblastic layer, then in the inner neuroblastic layer and at 9 weeks post-conception a bilaminar expression pattern. Expression was also noted within the developing optic stalk and optic disk. We identified a large cohort of IIN patients (n = 100), and performed sequence analysis which revealed 45 patients with FRMD7 mutations. Patients with FRMD7 mutations underwent detailed retinal imaging studies using ultrahigh-resolution optical coherence tomography. The tomograms were compared with a control cohort (n = 60). The foveal pit was significantly shallower in FRMD7 patients (P < 0.0001). The optic nerve head morphology was abnormal with significantly decreased optic disk area, retinal nerve fiber layer thickness, cup area and cup depth in FRMD7 patients (P < 0.0001). This study shows for the first time that abnormal afferent system development is associated with FRMD7 mutations and could be an important etiological factor in the development of nystagmus.

Mutations in FRMD7, a newly identified member of the FERM family, cause X-linked idiopathic congenital nystagmus.

Idiopathic congenital nystagmus is characterized by involuntary, periodic, predominantly horizontal oscillations of both eyes. We identified 22 mutations in FRMD7 in 26 families with X-linked idiopathic congenital nystagmus. Screening of 42 singleton cases of idiopathic congenital nystagmus (28 male, 14 females) yielded three mutations (7%). We found restricted expression of FRMD7 in human embryonic brain and developing neural retina, suggesting a specific role in the control of eye movement and gaze stability.

The clinical and molecular genetic features of idiopathic infantile periodic alternating nystagmus.

Periodic alternating nystagmus consists of involuntary oscillations of the eyes with cyclical changes of nystagmus direction. It can occur during infancy (e.g. idiopathic infantile periodic alternating nystagmus) or later in life. Acquired forms are often associated with cerebellar dysfunction arising due to instability of the optokinetic-vestibular systems. Idiopathic infantile periodic alternating nystagmus can be familial or occur in isolation; however, very little is known about the clinical characteristics, genetic aetiology and neural substrates involved. Five loci (NYS1-5) have been identified for idiopathic infantile nystagmus; three are autosomal (NYS2, NYS3 and NYS4) and two are X-chromosomal (NYS1 and NYS5). We previously identified the FRMD7 gene on chromosome Xq26 (NYS1 locus); mutations of FRMD7 are causative of idiopathic infantile nystagmus influencing neuronal outgrowth and development. It is unclear whether the periodic alternating nystagmus phenotype is linked to NYS1, NYS5 (Xp11.4-p11.3) or a separate locus. From a cohort of 31 X-linked families and 14 singletons (70 patients) with idiopathic infantile nystagmus we identified 10 families and one singleton (21 patients) with periodic alternating nystagmus of which we describe clinical phenotype, genetic aetiology and neural substrates involved. Periodic alternating nystagmus was not detected clinically but only on eye movement recordings. The cycle duration varied from 90 to 280 s. Optokinetic reflex was not detectable horizontally. Mutations of the FRMD7 gene were found in all 10 families and the singleton (including three novel mutations). Periodic alternating nystagmus was predominantly associated with missense mutations within the FERM domain. There was significant sibship clustering of the phenotype although in some families not all affected members had periodic alternating nystagmus. In situ hybridization studies during mid-late human embryonic stages in normal tissue showed restricted FRMD7 expression in neuronal tissue with strong hybridization signals within the afferent arms of the vestibulo-ocular reflex consisting of the otic vesicle, cranial nerve VIII and vestibular ganglia. Similarly within the afferent arm of the optokinetic reflex we showed expression in the developing neural retina and ventricular zone of the optic stalk. Strong FRMD7 expression was seen in rhombomeres 1 to 4, which give rise to the cerebellum and the common integrator site for both these reflexes (vestibular nuclei). Based on the expression and phenotypic data, we hypothesize that periodic alternating nystagmus arises from instability of the optokinetic-vestibular systems. This study shows for the first time that mutations in FRMD7 can cause idiopathic infantile periodic alternating nystagmus and may affect neuronal circuits that have been implicated in acquired forms.

Structural grading of foveal hypoplasia using spectral-domain optical coherence tomography a predictor of visual acuity?

PURPOSE: To characterize and grade the spectrum of foveal hypoplasia based on different stages of arrested development of the fovea. Grading was performed using morphologic findings obtained by ultra high-resolution spectral-domain optical coherence tomography. Best-corrected visual acuity (BCVA) was calculated for different grades. DESIGN: Observational case series. PARTICIPANTS AND CONTROLS: Sixty-nine patients with foveal hypoplasia (albinism, n = 34; PAX6 mutations, n = 10; isolated cases, n = 14; achromatopsia, n = 11) and 65 control subjects were examined. METHODS: A 7×7-mm retinal area was sampled using a 3-dimensional scanning protocol (743×75, A scans×B scans) with ultra high-resolution spectral-domain optical coherence tomography (SOCT Copernicus HR; 3-µm axial resolution). Gross morphologic abnormalities were documented. B-scans at the fovea were segmented using a longitudinal reflectivity profile. Logarithm of the minimum angle of resolution BCVA was obtained. MAIN OUTCOME MEASURES: Grading was based on presence or absence of foveal pit and widening of the outer nuclear layer (ONL) and outer segment (OS) at the fovea. Quantitative measurements were obtained for comparing atypical foveal hypoplasia in achromatopsia. Best-corrected visual acuity was compared with the grade of foveal hypoplasia. RESULTS: Four grades of foveal hypoplasia were distinguished: grade 1, shallow foveal pit, presence of ONL widening, presence of OS lengthening; grade 2, grade 1 but absence of foveal pit; grade 3, grade 2 but absence of OS lengthening; grade 4, grade 3 but absence of ONL widening. There was significant difference in visual acuity (VA) associated with each grade (P<0.0001). Grade 1 was associated with the best VA (median VA, 0.2), whereas grades 2, 3, and 4 were associated with progressively poorer VA with a median VA of 0.44, 0.60, and 0.78, respectively. The atypical features seen with foveal hypoplasia associated with achromatopsia were characterized by decreased retinal and ONL thickness and deeper foveal depth. CONCLUSIONS: A structural grading system for foveal hypoplasia was developed based on the stage at which foveal development was arrested, which helps to provide a prognostic indicator for VA and is applicable in a range of disorders associated with foveal hypoplasia. Atypical foveal hypoplasia in achromatopsia shows different characteristics. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Neuropsychological outcomes of children with Optic Pathway Glioma.

Optic Pathway Glioma (OPG) is a relatively common brain tumour in childhood; however, there is scarce understanding of neuropsychological sequelae in these survivors. In this study, 12 children with diagnosis of OPG before 6 years of age received a comprehensive standardised assessment of visual perception, general intelligence and academic achievement, using adjustments to visual materials of the tests, to examine the extent of concurrent impairment in these functional domains. Information about vision, clinical and socio-demographic factors were extracted from medical records to assess the associations of neuropsychological outcomes with clinical and socio-demographic factors. Children with OPG exhibited high within-patient variability and moderate group-level impairment compared to test norms. Visual perception was the most impaired domain, while scholastic progression was age-appropriate overall. For cognition, core verbal and visuo-spatial reasoning skills were intact, whereas deficits were found in working memory and processing speed. Visual function was associated with tasks that rely on visual input. Children with OPG are at moderate risk of neuropsychological impairment, especially for visual perception and cognitive proficiency. Future research should elucidate further the relative contribution of vision loss and neurofibromatosis type 1 co-diagnosis within a large sample.

Phenotypical characteristics of idiopathic infantile nystagmus with and without mutations in FRMD7.

Idiopathic infantile nystagmus (IIN) consists of involuntary oscillations of the eyes. The familial form is most commonly X-linked. We recently found mutations in a novel gene FRMD7 (Xq26.2), which provided an opportunity to investigate a genetically defined and homogeneous group of patients with nystagmus. We compared clinical features and eye movement recordings of 90 subjects with mutation in the gene (FRMD7 group) to 48 subjects without mutations but with clinical IIN (non-FRMD7 group). Fifty-eight female obligate carriers of the mutation were also investigated. The median visual acuity (VA) was 0.2 logMAR (Snellen equivalent 6/9) in both groups and most patients had good stereopsis. The prevalence of strabismus was also similar (FRMD7: 7.8%, non-FRMD7: 10%). The presence of anomalous head posture (AHP) was significantly higher in the non-FRMD7 group (P < 0.0001). The amplitude of nystagmus was more strongly dependent on the direction of gaze in the FRMD7 group being lower at primary position (P < 0.0001), compared to non-FRMD7 group (P = 0.83). Pendular nystagmus waveforms were also more frequent in the FRMD7 group (P = 0.003). Fifty-three percent of the obligate female carriers of an FRMD7 mutation were clinically affected. The VA's in affected females were slightly better compared to affected males (P = 0.014). Subnormal optokinetic responses were found in a subgroup of obligate unaffected carriers, which may be interpreted as a sub-clinical manifestation. FRMD7 is a major cause of X-linked IIN. Most clinical and eye movement characteristics were similar in the FRMD7 group and non-FRMD7 group with most patients having good VA and stereopsis and low incidence of strabismus. Fewer patients in the FRMD7 group had AHPs, their amplitude of nystagmus being lower in primary position. Our findings are helpful in the clinical identification of IIN and genetic counselling of nystagmus patients.

A case of Phoma fungal keratitis in a contact lens user.

Fungi of the genus Phoma are common plant pathogens and saprophytes and are rarely pathogenic to animals.

Autosomal-dominant nystagmus, foveal hypoplasia and presenile cataract associated with a novel PAX6 mutation.

Autosomal-dominant idiopathic infantile nystagmus has been linked to 6p12 (OMIM 164100), 7p11.2 (OMIM 608345) and 13q31-q33 (OMIM 193003). PAX6 (11p13, OMIM 607108) mutations can also cause autosomal-dominant nystagmus, typically in association with aniridia or iris hypoplasia. We studied a large multigenerational white British family with autosomal-dominant nystagmus, normal irides and presenile cataracts. An SNP-based genome-wide analysis revealed a linkage to a 13.4-MB region on chromosome 11p13 with a maximum lod score of 2.93. A mutation analysis of the entire coding region and splice junctions of the PAX6 gene revealed a novel heterozygous missense mutation (c.227C>G) that segregated with the phenotype and is predicted to result in the amino-acid substitution of proline by arginine at codon 76 p.(P76R). The amino-acid variation p.(P76R) within the paired box domain is likely to destabilise the protein due to steric hindrance as a result of the introduction of a polar and larger amino acid. Eye movement recordings showed a significant intrafamilial variability of horizontal, vertical and torsional nystagmus. High-resolution in vivo imaging of the retina using optical coherence tomography (OCT) revealed features of foveal hypoplasia, including rudimentary foveal pit, incursion of inner retinal layers, short photoreceptor outer segments and optic nerve hypoplasia. Thus, this study presents a family that segregates a PAX6 mutation with nystagmus and foveal hypoplasia in the absence of iris abnormalities. Moreover, it is the first study showing detailed characteristics using eye movement recordings of autosomal-dominant nystagmus in a multigenerational family with a novel PAX6 mutation.

Clinical and oculomotor characteristics of albinism compared to FRMD7 associated infantile nystagmus.

PURPOSE: Previous studies have found no difference between nystagmus characteristics associated with idiopathic infantile nystagmus (IIN) and that associated with albinism. The present aim is to compare the oculomotor characteristics and other associated clinical features of albinism and a genetically homogenous group of IIN volunteers where the nystagmus is associated with FRMD7 mutations. METHODS: Oculomotor characteristics and related clinical features between albinism (n = 52) and idiopathic nystagmus associated with FRMD7 mutations (FRMD7-IIN, n = 83) were compared. The nystagmus characteristics compared included amplitude, frequency, intensity of nystagmus, foveation characteristics, and waveform type. Other clinical features compared were strabismus, stereopsis and anomalous head posture. RESULTS: The FRMD7-IIN group contained a higher proportion of pendular waveform types compared with the albinism group (P < 0.0001). Nystagmus frequency was significantly lower in albinos (mean = 3.3 Hz, SD = 0.13 Hz) compared with the FRMD7-IIN group (mean = 4.3 Hz, SD = 0.18 Hz) (F = 14.5, P < 0.0001). Strabismus and anomalous head posture was seen in higher proportions in the albinism group, and stereopsis was worse compared with the FRMD7-IIN group (P ≪ 0.0001). CONCLUSIONS: Differences in nystagmus characteristics associated with albinism and those associated with FRMD7 mutations leading to IIN are described for the first-time. These findings may provide useful information in the future elucidation of mechanisms underlying the nystagmus associated with albinism and idiopathic infantile nystagmus.

Treatment of acquired periodic alternating nystagmus with memantine: a case report.

We report a case of acquired periodic alternating nystagmus associated with common variable immunodeficiency and cutaneous sarcoid. The patient was initially treated with baclofen with minimal subjective improvement. We found a significant improvement in the patient's symptoms and nystagmus intensity after treatment with memantine.

The prevalence of nystagmus: the Leicestershire nystagmus survey.

PURPOSE: Nystagmus, which can be infantile (congenital) or acquired, affects all ages. The prevalence of nystagmus in the general population is unknown. New genetic research and therapeutic modalities are emerging. Previous estimates have been based on wider ophthalmic epidemiologic studies within specific occupational or age groups. The authors carried out the first epidemiologic study to specifically establish the prevalence of nystagmus in Leicestershire and Rutland in the United Kingdom. METHODS: Three independent data sources identified persons with nystagmus from the hospital and community. The first was a hospital-based questionnaire and clinical survey (n = 238). The visually impaired services (n = 414) and education services (n = 193) in Leicestershire provided the second and third separately obtained community-based sources of information. Capture-recapture statistical analysis was used to estimate prevalence. RESULTS: The prevalence of nystagmus in the general population was estimated to be 24.0 per 10,000 population (95% confidence interval [CI], +/-5.3). The most common forms of nystagmus were neurologic nystagmus (6.8 per 10,000 population; 95% CI, +/-4.6), nystagmus associated with low vision such as congenital cataracts (4.2 per 10,000; 95% CI, +/-1.2), and nystagmus associated with retinal diseases such as achromatopsia (3.4 per 10,000 population; 95% CI, +/-2.1). Within ethnic groups, nystagmus was significantly more common in the white European population than in the Asian (Indian, Pakistani, other Asian backgrounds) population (P = 0.004). CONCLUSIONS: The findings suggest that nystagmus is more common in the general population than previously thought. This may be of significance in resource allocation and health care planning.

Congenital nystagmus: randomized, controlled, double-masked trial of memantine/gabapentin.

OBJECTIVE: Nystagmus consists of involuntary to and fro movements of the eyes. Although studies have shown that memantine and gabapentin can reduce acquired nystagmus, no drug treatment has been systematically investigated in congenital nystagmus. METHODS: We performed a randomized, double-masked, placebo-controlled study investigating the effects of memantine and gabapentin on congenital nystagmus over a period of 56 days. The primary outcome measure was logarithmic minimum angle of resolution (logMAR) visual acuity; the secondary outcome measures were nystagmus intensity and foveation, subjective questionnaires about visual function (VF-14) and social function. Analyses were by intention to treat. RESULTS: Forty-eight patients were included in the study. One patient in the placebo group dropped out. Patients were randomized into either a memantine group (n=16), gabapentin group (n=16), or placebo group (n=15). Mean visual acuity improvements showed a significant effect between treatment groups (F=6.2; p=0.004, analysis of variance) with improvement in both memantine and gabapentin groups. Participants with afferent visual defects showed poorer improvements in visual acuity to medication than those with apparently normal visual systems. However, eye movement recordings showed that both nystagmus forms improved in nystagmus intensity (F=7.7; p=0.001) and foveation (F=8.7; p=0.0007). Participants subjectively reported an improvement in vision after memantine and gabapentin treatment more often than in the placebo group (p=0.03). However, there were no significant differences between the treatment groups with visual function (VF-14) or social function questionnaires because all groups reported improvements. INTERPRETATION: Our findings show that pharmacological agents such as memantine and gabapentin can improve visual acuity, reduce nystagmus intensity, and improve foveation in congenital nystagmus.

Optic nerve sheath fenestration for intracranial hypertension associated with chronic inflammatory demyelinating polyneuropathy.

The authors report a case of papilledema in a 61-year-old woman with chronic demyelinating polyneuropathy. The cerebrospinal fluid protein level was elevated (2.68 to 4.51 g/L), as was the cerebro-spinal fluid opening pressure (27 to 40 cm H2O). A unilateral optic nerve sheath fenestration proved to be effective in preserving vision, and the papilledema resolved completely.