The spectrum of clinical presentation in haploinsufficiency of A20; a case report of a novel mutation in TNFAIP3 gene.

Haploinsufficiency of A20 was first described in 2016 as a new autoinflammatory disease that clinically presents as early-onset Behcet's disease. After the publication of the first 16 cases, more patients were diagnosed and described in the literature. The spectrum of clinical presentation has expanded. In this short report, we present a patient with a novel mutation in the TNFAIP3 gene. The clinical presentation included signs of an autoinflammatory disease with recurrent fever, abdominal pain, diarrhea, respiratory tract infections, and elevated inflammatory parameters. We will emphasize the importance of genetic testing, especially in patients with various clinical signs that do not fit a single autoinflammatory disease.

Electroretinography and optical coherence tomography reveal abnormal post-photoreceptoral activity and altered retinal lamination in patients with enhanced S-cone syndrome.

PURPOSE: To compare functional abnormalities of enhanced S-cone syndrome (ESCS), as examined using standard and extended electroretinography (ERG), with structural findings and retinal architecture obtained by spectral domain optical coherence tomography (SD-OCT). METHODS: Four patients with ESCS underwent standard full-field and multifocal ERGs, with extended S-cone and ON/OFF ERG protocols also performed. SD-OCT was also carried out, and longitudinal reflectivity profiles (LRPs) were calculated for the perifoveolar retina. RESULTS: All four patients exhibited pathognomonic full-field ERG findings for ESCS, with delayed responses of similar waveforms to the same intensity flash under both scotopic and photopic conditions. The amplitudes of the full-field ERGs showed considerable variation between patients, which were not related to the extent of the visual field defects. Multifocal ERGs reflected preserved central function in eyes with good visual acuity (Snellen visual acuity >0.7). The ERGs to S-cone-specific stimulation confirmed the expected predominant activity of the S-cone system in all four patients. The ON/OFF ERG recordings revealed abnormal presence of both ON-response and OFF-response activities in three patients; the remaining patient showed only OFF-response activity. SD-OCT showed a significantly thickened outer nuclear layer in all four patients, as obtained by LRP analysis. Furthermore, in the patient with selective preservation of the OFF-response activity, LRP showed reduced numbers of hyper-reflectivity sub-peaks in the inner plexiform layer. CONCLUSION: Patients with ESCS show characteristic full-field ERG waveform abnormality, predominance of S-cone ERG activity, and thickening of the outer nuclear layer on SD-OCT. Moreover, they can also show abnormal post-photoreceptor connectivity through S-cone-related OFF-bipolar cell activity.

Genetic risk for co-occurrence of type 1 diabetes and celiac disease is modified by HLA-C and killer immunoglobulin-like receptors.

The prevalence of celiac disease (CD) in patients with type 1 diabetes (T1D) has been reported to be 5-7 times higher than in the general population. Risk factors for co-occurrence of both diseases have not been entirely established. The aim of our study was to analyze possible impact of human leukocyte antigen (HLA) class I and killer cell immunoglobulin-like receptors (KIRs) on the co-occurrence of T1D and CD. We analyzed 67 patients with T1D, 68 patients with CD, 69 patients with both diseases (T1D+CD) and 130 controls. Statistical analysis was based on two tailed Fisher exact test with corrections for multiple testing. After stratification by DR3-DQ2, an association of HLA class I part of the COX haplotype (A1-B8-Cw7-DR3-DQ2) was not observed with each of the studied diseases separately, but it could be shown in case of the co-occurrence of T1D and CD. Only in the group of patients with coexisting diseases, the presence of HLA-C*07 (P = 8.65×10(-3) ) and HLA-B*08 (P = 0.03) but not HLA-A*01 increased the succeptibility. Our current data indicated that C*07, contributing C1 ligand (Pc = 3.67×10(-5) ) rather than B*08, that possesses no KIR ligand, could have an impact on the innate immunity rout of this susceptibility. The significant combination of C1-KIR2DL3 (Pc = 1.97×10(-4) ) observed in patients with coexisting diseases supports this hypotesis. Interestingly, no association was observed when C1 in combination with its stronger inhibitory receptor KIR2DL2 was investigated. Predominantly, weak inhibition in patients with coexisting T1D and CD could lead to a natural killer cell response, making them vulnerable for developing more than one autoimmune disease.

Characteristics of gastroesophageal reflux and potential risk of gastric content aspiration in children with cystic fibrosis.

OBJECTIVES: Increased gastroesophageal reflux (GER) is common in children with cystic fibrosis (CF). We studied the occurrence of acid, weakly acidic (WA), and weakly alkaline (WALK) reflux in children with CF and evaluated a possible surrogate marker for risk of gastric content aspiration. PATIENTS AND METHODS: Twenty-four children with CF underwent impedance-pH monitoring for detection of acid (pH < 4), WA (pH 4-7), and WALK-GER (pH > or = 7). In 11 children, cough was objectively recorded with esophageal manometry and the symptom association probability was calculated to determine the reflux-cough relation. Presence of bile acids (BA) was measured in the saliva of 65 patients with CF and 23 healthy children, respectively. RESULTS: Sixteen of the 24 children had increased GER (esophageal acid exposure). The majority of reflux events were acidic in nature. WA reflux was less common and WALK reflux was rare. The sequence reflux-cough was found in 8 of the 11 children and 1 of 11 children had a positive symptom association probability for reflux-cough. The sequence cough-reflux was found in only 3 of the 11 children. Only a small fraction of the total esophageal acid and volume exposure was secondary to cough. Twenty-three of the 65 children with CF had BA in saliva compared with none of the healthy controls. CONCLUSIONS: Although WA-GER is uncommon, acid GER is prevalent in children with CF. It is a primary phenomenon and is not secondary to cough. One third of the children with CF have BA in saliva, which may indicate an increased risk for aspiration. However, the impact of salivary BA and potential aspiration on CF pulmonary disease needs further investigation.

The co effect of prophylaxis and radiosynovectomy on bleeding episodes in haemophilic synovitis.

Prophylactic substitution treatment and radiosynoviorthosis have a leading role in preventing irreversible haemophilic arthropathy. The aim of the study was to evaluate the effects of prophylaxis treatment and radiosynovectomy on the length of intervals between subsequent haemorrhages in haemophilic patients. Thirty-three joints were treated with radiosynovectomy in 28 patients with bleeding disorders. (90)Y colloid was used in knees and (186)Re colloid for elbows, shoulders and ankles. Twenty patients were on prophylaxis. Joint X-rays were evaluated on the Pettersson scale between 0 (normal) and 13 (severe joint destruction). During an observation period (range 6-44 months) bleeding episodes were recorded and data statistically analysed. Before radiosynovectomy, increasing intensity of the prophylaxis 10% lengthens intervals between two haemorrhages by 1% (P < 0.05). In patients with a Pettersson score higher than nine, intervals between bleedings are shorter by 73% (P < 0.05), in comparison with patients with lower Pettersson scores of 0-5. After radiosynovectomy, the length of the first non-bleeding interval increased by 120% (to 60 days) in comparison with the intervals before the procedure (P < 0.001). But, in the following year and half, every subsequent non-bleeding interval was 8% shorter (P < 0.1). In that period, prophylaxis shortened the non-bleeding interval by 1.7% (P < 0.05) per 10% increase of its intensity. Radiosynovectomy is more efficient in patients with less affected joints and is less efficient in younger patients. Prophylaxis reduced time between the bleedings episodes after isotope application. Before radiosynovectomy, prophylaxis reduces the number of haemorrhages. Our findings support data previously published by Rodriguez-Merchan et al. [J Thromb Haemost, 5 (2007) P-W-126].

Viability of human chondrocytes in an ex vivo model in relation to temperature and cartilage depth.

Chondrocytes in human articular cartilage remain viable post-mortem. It has however not been established yet how the storage temperature affects their survival, which is essential information when post-mortem cartilage is used for toxicologic studies. Our aim was to construct a simple model of explanted knee cartilage and to test the influences of time and temperature on the viability of chondrocytes in the ex vivo conditions. Osteochondral cylinders were procured from the cadaveric femoral condyles. The cylinders were embedded in water-tight rubber tubes, which formed separate chondral and osteal compartments. Tubes were filled with normal saline, without additives, to keep chondrocytes under close-to-normal conditions. The samples were divided into two groups stored at 4 degrees C and 35 degrees C, respectively. Three samples of each of these two groups were analysed at the time of removal, and then three and nine days later. Images of Live-Dead staining were scanned by a confocal laser microscope. Count of viable chondrocytes in four regions, from surface to bone, was obtained using image analysis software. The regression model revealed that the number of viable chondrocytes decreased every day by 19% and that an increase in temperature by 1 degree C decreased their viability by 5.8%. The temperature effect fell by 0.2 percentage points for every 100 microm from the surface to the bone. Herein we demonstrate that chondrocytes remain viable in the ex vivo model of human knee cartilage long enough to be able to serve as a model for toxicologic studies. Their viability is, however, significantly influenced by time and temperature.

Optic neuritis in children--clinical and electrophysiological follow-up.

Optic neuritis (ON) in children usually presents with visual loss, relative afferent pupillary defect (RAPD), abnormal optic disc appearance, defects of visual field and colour vision, as well as with abnormalities of visual evoked potentials (VEP). Both, clinical and VEP parameters, improve after the attack; the time until recovery, however, is as yet unknown. The aim of this study was to follow-up children with ON for 1 year and to determine clinical and VEP recovery. Twelve children (six with bilateral, six with unilateral ON) were studied in the acute phase and systematically followed-up for 1 year. The results show that initially, visual acuity was diminished in all eyes, while after 1 year, in only 14% of them. Optic disc appearance was abnormal in 83.3% of the eyes in the acute phase, and in 85% after 1 year. At the disease onset RAPD could be detected in 67%, visual field defects in 58.5%, and colour vision defects in 50% of eyes, but none of these abnormalities persisted in any eye until the end of study. VEP were abnormal in 83% of eyes in the acute phase and in 56% at the final follow-up (at 6 or 12 months). VEP normalization, when occurred, was mostly observed during the first 6 months. Complete clinical and VEP recovery was observed in three children. Both, clinical and electrophysiological recovery in children with ON were relatively substantial and fast within the first year. VEP improvement may indicate better prognosis.

Pattern ERG and psychophysical functions in Best's disease.

The aim of the study was to asses the neurosensory retinal function in 12 patients (24 eyes) with different stages of Best's disease, by determining how pattern and full field flash ERG responses were related to visual acuity, stage of disease and extent of visual field loss. All patients had typically abnormal EOG responses and normal full field-flash ERG responses. Patients were stratified in two groups according to visual acuity. In the first group 12 eyes with visual acuity better than 0.5, all amplitudes and latencies of PERG P50 and N95 responses were in the normal range. Small central scotoma was detected by static perimetry in four of these eyes. In the second group of 12 eyes with visual acuity 0.5 or less, PERG showed reduced both P50 and N95 amplitudes in five eyes, and N95 solely, in two eyes. All patients had central scotomas detected by static perimetry. Progression of the disease, seen in deterioration of visual acuity and progression of central visual field defects, corresponded well with reduction of both PERG P50 and N95 amplitudes. There was no correlation found between visual acuity and EOG responses. Our results show that in Best's distrophy, pattern ERG is getting abnormal with progression of the disease, indicating relative preservation of neurosensory retina in initial stages of the disease. In contrast to EOG - being abnormal in all the patients regardless of the stage of disease - and full field-flash ERG - being normal in most of the patients - PERG gives opportunity for electrophysiological determination of the progression of the disease.

Visual electrophysiology in children with tumours affecting the visual pathway. Case reports.

In 9 children (8-14 years of age) with orbital, suprasellar or postchiasmal tumours, visual loss was studied by visual electrophysiology in relation to ophthalmologic and neuroimaging findings. Pattern electroretinography (PERG) and pattern visual evoked potentials (PVEP) to full and half-field pattern-reversal stimulation were recorded and PERG and PVEP changes were related to the tumour location. PERG wave P50 attenuation was found associated with the central retinal dysfunction in the child with orbital rhabdomyosarcoma; PVEP wave P100 delay was associated with the optic nerve dysfunction in a child with retrobulbar chondrosarcoma and in a child with optic nerve glioma; PVEP wave P100 asymmetry was associated with the crossed fibers dysfunction in a child with hypothalamic germinoma, and PVEP wave P100 uncrossed asymmetry was associated with postchiasmal dysfunction in children with postchiasmal tumours (one with pilocytic astrocytoma and two with angioma). On the other hand, normal PERG suggested that there was no central retinal dysfunction in a child with pleomorphic adenoma of the lacrimal gland, and normal PVEP to full and half-field stimulation excluded visual pathway dysfunction at the chiasm in a child with suprasellar arachnoidal cyst. Follow-up was useful in indicating whether visual dysfunction was progressive or not. We conclude that PERG and PVEP findings contributed to understanding whether the dysfunction originated was at the retina, in the optic nerve, chiasm or postchiasmal pathway.

ERG and VEP follow-up study in children with Leber's congenital amaurosis.

PURPOSE: Our prospective clinical and electrophysiological study of children suspected of Leber's congenital amaurosis (LCA) was aimed to follow-up the course of their visual dysfunction. METHODS: Electroretinography (ERG) and visual evoked potentials (VEP) to white flash stimulation were simultaneously recorded in 9 children at least twice. RESULTS: The first flash ERG and flash VEP recordings were performed when children were 3-17 months old (mean age 7.6 months). Flash ERG was not recordable in 8 children; flash VEP to binocular stimulation could not be detected in 3, was delayed in 2, attenuated in 2, both attenuated and delayed in 1, and without evident abnormality in 1 of the 9 children. On the last examination (mean age 33.8 months) flash VEP activity was recordable in all children, while flash ERG was recordable in 1. Electrophysiological follow-up (mean duration 26.2 months) showed no deterioration of flash VEP in 8 children. CONCLUSION: In children of LCA simultaneous recording of flash ERG and flash VEP in alert children was helpful to indicate the nature of the visual problem for diagnostic and follow-up purposes.

Visual evoked magnetic responses to central and peripheral stimulation: simultaneous VEP recordings.

Visual evoked magnetic field (VEF) and visual evoked potentials (VEP) in response to pattern reversal left half-field central (0-2 degrees, 0-5 degrees) and to left half-field peripheral stimulation (2-15 degrees, 5-15 degrees) were simultaneously recorded in 10 normal subjects. The aim was to localize the origin of the largest wave around 100 ms. By comparing the magnetic evoked 100m wave and electric evoked P100 wave, we found that the response to the small central field (0-2 degrees) stimulation was clearly evident in the VEP and not in the VEF, while the response to the peripheral field (2-15 degrees, 5-15 degrees) stimulation was clearly present in both the VEP and VEF. Our findings show that in contrast to the already recognized predominantly macular origin of VEP activity, VEF activity has a peripheral rather than macular prevalence. Our VEF findings are related to the retinotopic organization of the visual cortex; the 100m dipole to the central field (0-5 degrees) was localized more (1.04 +/- 0.84 cm) posterior than was the 100m dipole to peripheral stimulation (5-15 degrees). The localization of 100m dipoles superimposed on magnetic resonance images (MRI) to central stimuli showed interindividual variations that were in agreement with the known variability of the central field representation in the striate cortex: on the convexity of the occipital pole, in the outer surface of the occipital lobe, and around the calcarine fissure of the right hemisphere. In contrast, following peripheral stimulation, the 100m dipole was located along the medial surface of the hemisphere or in the calcarine fissure. Our results suggest that the main origin of the largest wave around l00ms in response to pattern reversal stimuli is in the striate cortex.

Simultaneous pattern electroretinogram and visual evoked potential recordings in dyslexic children.

To help clarify the conflicting evidence of neurophysiologic abnormalities in children with reading problems (dyslexia), we examined pattern electroretinograms and visual evoked potentials to stimulation with checks of 24', 49' and 180', each at 5%, 42% and 100% contrast, in a group of dyslexic children and a group of normal (i.e., normally reading) children. Neurophysiologic difference between the groups was restricted to the visual evoked potential, which showed a significant prolongation of the P100 wave in dyslexic children at the highest contrast (100%) and the smallest checks (24'). There was no significant difference between normal and dyslexic children in the P50 and N95 pattern electroretinogram waves. These results support the assumption of a visual deficit in dyslexic children. However, they are not consistent with the evidence of an isolated deficit of the magnocellular function, which, theoretically, would cause more prominent visual evoked potential changes to lower contrast and the largest check stimuli.

Do visual neurophysiological tests reflect magnocellular deficit in dyslexic children?

To address the question of a possible magnocellular visual deficit in children with reading problems (dyslexia), we examined pattern ERG and VEP responses to stimulation with checks of 24', 49' and 180' in size and of 5%, 42% and 100% contrast level. Neurophysiological difference between children with reading problems and those without them was found confined to VEP which showed a significant prolongation of P100 wave in dyslexic children at highest contrast (100%) and smallest checks (24'). Pattern ERG was normal. These results support the assumption of a visual deficit in dyslexic children. However, they are not consistent with an isolated deficit of the magnocellular function, which, theoretically, would cause VEP changes to lower contrast and largest check stimuli.

Electrodiagnostics of chiasmal compressive lesions.

Recording of visual evoked potentials (VEPs) is not yet a routine test in patients with suspected chiasmal compressive lesions, but has proved useful to a clinician in assessing and following-up visual pathway dysfunctions. Abnormalities of VEPs can be found even in patients without clinical evidence of the visual impairment: VEP delays and alterations of the waveform, asymmetric distribution in one eye or in both eyes (crossed asymmetry) can indicate chiasmal compressive lesion. Simultaneous recording of pattern electroretinograms (PERGs) can additionally provide useful information about the patient's cooperation as well as about eventual retrograde degeneration of the ganglion cells. Electrophysiologic tests can be regarded as an integral part of diagnostic procedures--ocular diagnostic tests and neuroimaging--in suspected compressive lesions of the optic chiasm.

A VEP study of the visual pathway function in compressive lesions of the optic chiasm. Full-field versus half-field stimulation.

Changes of the pattern reversal visual evoked potentials (VEPs) to half- and full-field stimulation in 50 patients with compressive lesions of the optic chiasm are presented. Temporal half-field stimulation yielded abnormal responses in 85% of the eyes, showing non-recordable P100 in 50% of eyes, while in 35% the P100 was significantly attenuated or delayed. With nasal half-field the percentage of all detectable abnormalities was lower (36% of the eyes). Full-field stimulation revealed VEP abnormalities in 74% of eyes and therefore proved less sensitive than the half-field stimulation. This study adds new evidence that half-field stimulation can be an important adjunct for assessing the function of the optic chiasm.

Electrophysiologic evaluation of the visual pathway in children. Case reports.

Clinical findings and results of electrophysiologic evaluation of the visual pathway were studied in seven children ranging in age from 10 months to 13 years. Using skin electrodes for electroretinographic and visual evoked potential testing, we obtained reliable results without sedation or pupil dilation. The half-field stimulation was indispensable for localizing lesions along the visual pathway and thus for specific diagnosis.

Central fiber contribution to W-shaped visual evoked potentials in patients with optic neuritis.

We studied W-shaped waveforms that occurred in full-field responses to pattern large-field stimulation in patients who had optic neuritis. Affected eyes showed no absolute scotomata; visual acuity was normal at the time of recording. To evaluate the contribution of macular- and paramacular-derived components to the development of the W-shaped waveforms in the patients, half-field and central full-field stimulation was used. The responses were compared with those obtained with the use of experimental scotomata in healthy subjects. The W-shaped waveforms recorded in the patients closely resembled the responses observed in healthy subjects after the introduction of experimental scotomata. In all affected eyes, half-field stimulation showed absence of the ipsilateral P100 component or its interaction with the P135 component. Enhanced paramacular N105 and P135 components were seen over the contralateral hemisphere. Responses to central full-field stimulation were an attenuated and prolonged P100 in the majority of affected eyes. Results of our study showed that W-shaped waveforms in response to large full-field stimulation may reflect impaired function of macular fibers. These electrophysiologic findings, however, were not always associated with evidence of a central field defect demonstrated by Friedmann perimetry.

Visual evoked potential abnormalities in chiasmal lesions.

Pattern reversal visual evoked potentials (VEPs) were recorded from 38 patients with lesions affecting the chiasmal area. Lesions were confirmed by computer tomography and all patients had ophthalmologic examination. VEPs to full-field stimulation (0-16 degrees r) were compared with those obtained with half-field stimulation. Changes in VEPs were seen as a nonrecordable or attenuated P 100 (abnormal amplitude ratio) or as a prolonged P 100. Analysis of the records showed that temporal half-field stimulation (crossed fibers) yielded a higher rate of abnormal responses (80%) than full-field stimulation (66%). The most frequent abnormality in the former stimulation was a nonrecordable P 100 (42%) and in the latter an abnormal amplitude ratio of P 100 (41%). When the uncrossed fibers were stimulated with the nasal half-field, abnormalities were detected in 32% of responses. Lesions in the region of the sella turcica were also associated with a high incidence of delayed responses (39% of patients when crossed fibers were stimulated). However, the magnitude of the delays was smaller (1-32 ms) compared with delays in patients with demyelinating disease. Findings of this study show that half-field stimulation assists in the interpretation of responses to full-field stimulation. In addition, half-field stimulation can reveal abnormalities that are not detected with full-field stimulation.

Pattern electroretinogram recorded by skin electrodes in early ocular hypertension and glaucoma.

Diagnostic value of transient pattern electroretinogram (PERG), recorded by skin electrodes, was compared with Goldmann perimetry in cases of ocular hypertension and glaucoma. According to the assumption that the PERG mostly reflects activity of the retinal ganglion cells, and histological evidence that 30-50% atrophy of the retinal ganglion cells is necessary to cause defects in visual field, we wanted to assess if i) this method could be more sensitive in detecting early glaucomatous damage than routine Goldmann perimetry in eyes with normal or only borderline elevated intraocular pressure in the time of PERG recording (first group of patients), and ii) how the PERG amplitude corresponds to ganglion cell loss, expected in the eyes with already detectable initial glaucomatous visual field defects, according to Goldmann II/2 isopter, with normal or borderline elevated intraocular pressure in the time of PERG recording (second group). In the group with no visual field defects subnormal amplitude of the major positive component of the PERG, N1-P1, was detected in three of 30 eyes (10%), while in the group with initial visual field defects N1-P1 amplitude was subnormal in 6 of 11 eyes (54%). The amplitude of the major negative PERG component, P1-N2, was found normal in all eyes of the first group and subnormal in 5 eyes (45%) of the second group.

Occipital distribution of foveal half-field responses.

Foveal left and right half-field responses were recorded in six subjects (12 half-fields) and compared with wide half-field responses. In the foveal responses a general trend was seen for the negative-positive-negative (NPN) complex to extend to the contralateral channels, replacing the contralateral positive-negative-positive (PNP) complex found with wide half-field stimulation. Many individual variations in foveal response morphology were seen, which may be understood in terms of anatomical variation. Individual differences between foveal half-fields in the same subject may be as great as those between subjects.