Evaluation of retinal nerve fiber layer thickness measurements using optical coherence tomography in patients with tobacco-alcohol-induced toxic optic neuropathy

Three patients with progressive visual loss, chronic alcoholism and tabagism were submitted to a complete neuro-ophthalmic examination and to retinal nerve fiber layer (RNFL) measurements using optical coherence tomography (OCT) scanning. Two patients showed marked RNFL loss in the temporal sector of the optic disc. However, a third patient presented RNFL measurements within or above normal limits, based on the Stratus-OCT normative database. Such findings may be due to possible RNFL edema similar to the one that may occur in the acute phase of toxic optic neuropathies. Stratus-OCT was able to detect RNFL loss in the papillomacular bundle of patients with tobacco-alcohol-induced toxic optic neuropathy. However, interpretation must be careful when OCT does not show abnormality in order to prevent diagnostic confusion, since overestimation of RNFL thickness measurements is possible in such cases.

Using frequency-doubling perimetry to detect optic neuropathy in patients with Graves` orbitopathy

to test the ability of frequency-doubling technology (FDT) perimetry to detect dysthyroid optic neuropathy (DON). Fifteen eyes of 15 patients with DON and 15 healthy control eyes were studied. Eligible eyes had a diagnosis of DON based on visual field abnormalities on standard automated perimetry and had visual acuity better than 20/30. FDT testing was performed using both the C-20-5 screening test and the C-20 full-threshold test. Normal and DON eyes were compared with regard to FDT mean sensitivity. Sensitivity ranges were 40.0%-86.7% for the screening test, and 53.3%-100.0% (total deviation) and 20.0-93.3 (pattern deviation) for the C-20 threshold test. The corresponding specificity ranges were 86.7-100.0, 33.3-93.3, and 26.7-100.0, respectively. The best sensitivity/specificity ratios were for one abnormal point depressed < 5% in the screening test (86.7%/86.7%), one point depressed < 1% in the total deviation analysis (80.0%/86.7%), and one point depressed < 2% in the pattern deviation analysis (80.0%/86.7%). DON eyes presented significantly lower than normal average sensitivity in the central, pericentral, and peripheral areas. FDT perimetry is a useful screening tool for DON in eyes with normal or only slightly reduced visual acuity.

Multi-system neurological disease is common in patients with OPA1 mutations

Additional neurological features have recently been described in seven families transmitting pathogenic mutations in OPA1, the most common cause of autosomal dominant optic atrophy. However, the frequency of these syndromal `dominant optic atrophy plus` variants and the extent of neurological involvement have not been established. In this large multi-centre study of 104 patients from 45 independent families, including 60 new cases, we show that extra-ocular neurological complications are common in OPA1 disease, and affect up to 20% of all mutational carriers. Bilateral sensorineural deafness beginning in late childhood and early adulthood was a prominent manifestation, followed by a combination of ataxia, myopathy, peripheral neuropathy and progressive external ophthalmoplegia from the third decade of life onwards. We also identified novel clinical presentations with spastic paraparesis mimicking hereditary spastic paraplegia, and a multiple sclerosis-like illness. In contrast to initial reports, multi-system neurological disease was associated with all mutational subtypes, although there was an increased risk with missense mutations [odds ratio = 3.06, 95% confidence interval = 1.44-6.49; P = 0.0027], and mutations located within the guanosine triphosphate-ase region (odds ratio = 2.29, 95% confidence interval = 1.08-4.82; P = 0.0271). Histochemical and molecular characterization of skeletal muscle biopsies revealed the presence of cytochrome c oxidase-deficient fibres and multiple mitochondrial DNA deletions in the majority of patients harbouring OPA1 mutations, even in those with isolated optic nerve involvement. However, the cytochrome c oxidase-deficient load was over four times higher in the dominant optic atrophy + group compared to the pure optic neuropathy group, implicating a causal role for these secondary mitochondrial DNA defects in disease pathophysiology. Individuals with dominant optic atrophy plus phenotypes also had significantly worse visual outcomes, and careful surveillance is therefore mandatory to optimize the detection and management of neurological disability in a group of patients who already have significant visual impairment.

Novel mutations of the BSCL2 and AGPAT2 genes in 10 families with Berardinelli-Seip congenital generalized lipodystrophy syndrome

P>Context Congenital generalized lipodystrophy, or Berardinelli-Seip syndrome, is a rare autosomal recessive disease caused by mutations in either the BSCL2 or AGPAT2 genes. This syndrome is characterized by an almost complete loss of adipose tissue usually diagnosed at birth or early infancy resulting in apparent muscle hypertrophy. Common clinical features are acanthosis nigricans, hepatomegaly with or without splenomegaly and high stature. Acromegaloid features, cardiomyopathy and mental retardation can also be present. Design We investigated 11 kindreds from different geographical areas of Brazil (northeast and southeast). All coding regions as well as flanking intronic regions of both genes were examined. Polymerase chain reaction (PCR) amplifications were performed using primers described previously and PCR products were sequenced directly. Results Four AGPAT2 and two BSCL2 families harboured the same set of mutations. BSCL2 gene mutations were found in the homozygous form in four kindreds (c.412C > T c.464T > C, c.518-519insA, IVS5-2A > G), and in two kindreds compound mutations were found (c.1363C > T, c.424A > G). In the other four families, one mutation of the AGPAT2 gene was found (IVS3-1G > C and c.299G > A). Conclusions We have demonstrated four novel mutations of the BSCL2 and AGPAT2 genes responsible for Berardinelli-Seip syndrome and Brunzell syndrome (AGPAT2-related syndrome).

Color Doppler imaging of the superior ophthalmic vein in different clinical forms of Graves` orbitopathy

To compare color Doppler imaging (CDI) parameters of the superior ophthalmic vein (SOV) in patients with Graves` orbitopathy (GO) and in normal controls. Forty-three GO patients and 14 normal controls underwent CDI of the SOV. Patients had either fibrotic (lipogenic or myogenic) or congestive orbitopathy. The findings for each group were compared. Fifty-eight orbits with fibrotic orbitopathy, 28 with congestive orbitopathy, and 28 from controls, were studied. In the congestive group, SOV flow was detected in 13, undetectable in 11, and reversed in four orbits; in the fibrotic group, it was present in 41 and undetectable in 17 orbits. In normal controls, SOV flow was detected in 25 and undetectable in three orbits. The differences among the three groups were significant. There was also a significant difference between controls and the congestive GO orbits but not between the fibrotic group and the other two groups. Fibrotic myogenic orbitopathy patients displayed a significantly smaller SOV flow than patients with lipogenic orbitopathy. SOV was significantly reduced in orbits with congestive GO or with myogenic fibrotic GO, but not in orbits with fibrotic lipogenic orbitopathy. SOV congestion may be a contributing pathogenic factor in both congestive and fibrotic myogenic Graves` orbitopathy.

Motor and functional evaluation of patients with spastic paraplegia, optic atrophy, and neuropathy (SPOAN)

Spastic paraplegia, optic atrophy, and neuropathy (SPOAN) is an autosomal recessive complicated form of hereditary spastic paraplegia, which is clinically defined by congenital optic atrophy, infancy-onset progressive spastic paraplegia and peripheral neuropathy. In this study, which included 61 individuals (age 5-72 years, 42 females) affected by SPOAN, a comprehensive motor and functional evaluation was performed, using modified Barthel index, modified Ashworth scale, hand grip strength measured with a hydraulic dynamometer and two hereditary spastic paraplegia scales. Modified Barthel index, which evaluate several functional aspects, was more sensitive to disclose disease progression than the spastic paraplegia scales. Spasticity showed a bimodal distribution, with both grades 1 (minimum) and 4 (maximum). Hand grip strength showed a moderate inverse correlation with age. Combination of early onset spastic paraplegia and progressive polyneuropathy make SPOAN disability overwhelming.

Beyond neuropathy in hereditary sensory and autonomic neuropathy type V: cognitive evaluation

Background and purpose: Hereditary sensory and autonomic neuropathy ( HSAN) type V is a very rare disorder. It is characterized by the absence of thermal and mechanical pain perception caused by decreased number of small diameter neurons in peripheral nerves. Recent genetic studies have pointed out the aetiological role of nerve growth factor beta, which is also involved in the development of the autonomic nervous system and cholinergic pathways in the brain. HSAN type V is usually reported not to cause mental retardation or cognitive decline. However, a structured assessment of the cognitive pro. le of these patients has never been made. Methods and results: We performed a throughout evaluation of four HSAN type V patients and compared their performance with 37 normal individuals. Our patients showed no cognitive deficits, not even mild ones. Discussion and Conclusions: Although newer mutations on this and related disorders are continuously described, their clinical characterization has been restricted to the peripheral aspects of these conditions. A broader characterization of this rare disorder may contribute to better understand the mechanisms of the nociceptive and cognitive aspects of pain.

Spastic Paraplegia, Optic Atrophy, and Neuropathy: New Observations, Locus Refinement, and Exclusion of Candidate Genes

SPOAN is an autosomal recessive neurodegenerative disorder which was recently characterized by our group in a large inbred Brazilian family with 25 affected individuals. This condition is clinically defined by: 1. congenital optic atrophy; 2. progressive spastic paraplegia with onset in infancy; and 3. progressive motor and sensory axonal neuropathy. Overall, we are now aware of 68 SPOAN patients (45 females and 23 males, with age ranging from 5 to 72 years), 44 of which are presented here for the first time. They were all born in the same geographic micro region. Those 68 patients belong to 43 sibships, 40 of which exhibit parental consanguinity. Sixty-one patients were fully clinically evaluated and 64 were included in the genetic investigation. All molecularly studied patients are homozygotes for D11S1889 at 11q13. This enabled us to reduce the critical region for the SPOAN gene from 4.8 to 2.3 Mb, with a maximum two point lod score of 33.2 (with marker D11S987) and of 27.0 (with marker D11S1889). Three genes located in this newly defined critical region were sequenced, but no pathogenic mutation was detected. The gene responsible for SPOAN remains elusive.

Inbreeding levels in Northeast Brazil: strategies for the prospecting of new genetic disorders

A new autosomal recessive genetic condition, the SPOAN syndrome (an acronym for spastic paraplegia, optic atrophy and neuropathy syndrome), was recently discovered in an isolated region of the State of Rio Grande do Norte in Northeast Brazil, in a population that was identified by the IBGE (Brazilian Institute of Geography and Statistics) as belonging to the Brazilian communities with the highest rates of "deficiencies" (Neri, 2003), a term used to describe diseases, malformations, and handicaps in general. This prompted us to conduct a study of consanguinity levels in five of its municipal districts by directly interviewing their inhabitants. Information on 7,639 couples (corresponding to about 40% of the whole population of the studied districts) was obtained. The research disclosed the existence of very high frequencies of consanguineous marriages, which varied from about 9% to 32%, suggesting the presence of a direct association between genetic diseases such as the SPOAN syndrome, genetic drift and inbreeding levels. This fact calls for the introduction of educational programs for the local populations, as well as for further studies aiming to identify and characterize other genetic conditions. Epidemiological strategies developed to collect inbreeding data, with the collaboration of health systems available in the region, might be very successful in the prospecting of genetic disorders.

Simultaneous preconcentration of copper, zinc, cadmium, and nickel in water samples by cloud point extraction using 4-(2-pyridylazo)-resorcinol and their determination by inductively coupled plasma optic emission spectrometry

A procedure for simultaneous separation/preconcentration of copper. zinc, cadmium, and nickel in water samples, based on cloud point extraction (CPE) as a prior step to their determination by inductively coupled plasma optic emission spectrometry (ICP-OES), has been developed. The analytes reacted with 4-(2-pyridylazo)-resorcinol (PAR) at pH 5 to form hydrophobic chelates, which were separated and preconcentrated in a surfactant-rich phase of octylphenoxypolyethoxyethanol (Triton X-I 14). The parameters affecting the extraction efficiency of the proposed method, such as sample pH, complexing agent concentration, buffer amount, surfactant concentration, temperature, kinetics of complexation reaction, and incubation time were optimized and their respective values were 5, 0.6 mmol L(-1). 0.3 mL, 0.15% (w/v), 50 degrees C, 40 min, and 10 min for 15 mL of preconcentrated solution. The method presented precision (R.S.D.) between 1.3% and 2.6% (n = 9). The concentration factors with and without dilution of the surfactant-rich phase for the analytes ranged from 9.4 to 10.1 and from 94.0 to 100.1, respectively. The limits of detection (L.O.D.) obtained for copper, zinc, cadmium, and nickel were 1.2, 1.1, 1.0. and 6.3 mu g L(-1), respectively. The accuracy of the procedure was evaluated through recovery experiments on aqueous samples. (C) 2009 Published by Elsevier B.V.

Development and fabrication of an optimized thermo-electro-optic device using a Mach-Zehnder interferometer

The development and fabrication of a thermo-electro-optic sensor using a Mach-Zehnder interferometer and a resistive micro-heater placed in one of the device`s arms is presented. The Mach-Zehnder structure was fabricated on a single crystal silicon substrate using silicon oxynitride and amorphous hydrogenated silicon carbide films to form an anti-resonant reflective optical waveguide. The materials were deposited by Plasma enhanced chemical vapor deposition technique at low temperatures (similar to 320 degrees C). To optimize the heat transfer and increase the device response with current variation, part of the Mach-Zehnder sensor arm was suspended through front-side bulk micromachining of the silicon substrate in a KOH solution. With the temperature variation caused by the micro-heater, the refractive index of the core layer of the optical waveguide changes due to the thermo-optic effect. Since this variation occurs only in one of the Mach-Zehnder`s arm, a phase difference between the arms is produced, leading to electromagnetic interference. In this way, the current applied to the micro-resistor can control the device output optical power. Further, reactive ion etching technique was used in this work to define the device`s geometry, and a study of SF6 based etching rates on different composition of silicon oxynitride films is also presented. (C) 2007 Elsevier B.V. All rights reserved.

Hereditary hemochromatosis: Mutations in genes involved in iron homeostasis in Brazilian patients

Background: p.C282Y mutation and rare variants in the HFE gene have been associated with hereditary hemochromatosis (HH). HH is also caused by mutations in other genes, such as the hemojuvelin (HJV), hepcidin (HAMP), transferrin receptor 2 (TFR2) and ferroportin (SLC40A1). The low rate homozygous p.C282Y mutation in Brazil is suggestive that mutations in non-HFE genes may be linked to HH phenotype. Aim: To screen exon-by-exon DNA sequences of HFE, HJV, HAMP, TFR2 and SLC40A1 genes to characterize the molecular basis of HH in a sample of the Brazilian population. Materials and methods: Fifty-one patients with primary iron overload (transferrin saturation >= 50% in females and >= 60% in males) were selected. Subsequent bidirectional DNA sequencing of HFE, HJV, HAMP, TFR2 and SLC40A1 exons was performed. Results: Thirty-seven (72.5%) out of the 51 patients presented at least one HFE mutation. The most frequent genotype associated with HH was the homozygous p.C282Y mutation (n = 11, 21.6%). In addition, heterozygous HFE p.S65C mutation was found in combination with p.H63D in two patients and homozygous HFE p.H63D was found in two patients as well. Sequencing in the HJV and HAMP genes revealed HJV p.E302K, HJV p.A310G, HJV p.G320V and HAMP p.R59G alterations. Molecular and clinical diagnosis of juvenile hemochromatosis (homozygous form for the HJV p.G320V) was described for the first time in Brazil. Three TFR2 polymorphisms (p.A75V, p.A617A and p.R752H) and six SLC40A1 polymorphisms (rs13008848, rs11568351, rs11568345, rs11568344, rs2304704, rs11568346) and the novel mutation SLC40A1 p.G204S were also found. Conclusions: The HE p.C282Y in homozygosity or in heterozygosity with p.H63D was the most frequent mutation associated with HH in this sample. The HJV p.E302K and HAMP p.R59G variants, and the novel SLC40A1 p.G2045 mutation may also be linked to primary iron overload but their role in the pathophysiology of HH remain to be elucidated. (C) 2011 Elsevier Inc. All rights reserved.

Trigeminal pain and quantitative sensory testing in painful peripheral diabetic neuropathy

Objective: To evaluate patients with Diabetes Mellitus type 2 and painful peripheral neuropathy in order to investigate oral complaints and facial somatosensory findings. Research design and methods: Case-control study; 29 patients (12 women, mean age 57.86 yo) with Diabetes Mellitus type 2 and 31 age-gender-matched controls were evaluated with a standardized protocol for general characteristics, orofacial pain, research diagnostic criteria for temporomandibular disorders, visual analogue scale and McGill Pain questionnaire, and a systematic protocol of quantitative sensory testing for bilateral facial sensitivity at the areas innervated by the trigeminal branches, which included the thermal detection by ThermoSensi 2, tactile evaluation with vonFrey filaments, and superficial pain thresholds with a superficial algometer (Micromar). Statistical analysis was performed with Wilcoxon, chi-square, confidence intervals and Spearman (p < 0.05). Results: Orofacial pain was reported by 55.2% of patients, and the most common descriptor was fatigue (50%); 17.2% had burning mouth. Myofascial temporomandibular disorders were diagnosed in 9(31%) patients. The study group showed higher sensory thresholds of pain at the right maxillary branch (p = 0.017) but sensorial differences were not associated with pain (p = 0.608). Glycemia and HbA(1c) were positively correlated with the quantitative sensory testing results of pain (p < 0.05) and cold (p = 0.044) perceptions. Higher pain thresholds were correlated with higher glycemia and glycated hemoglobin (p = 0.027 and p = 0.026). Conclusions: There was a high prevalence of orofacial pain and burning mouth was the most common complaint. The association of loss of pain sensation and higher glycemia and glycated hemoglobin can be of clinical use for the follow-up of DM complications. (C) 2010 Elsevier Ltd. All rights reserved.

Prevalence of diabetic peripheral neuropathy and relation to glycemic control therapies at baseline in the BARI 2D cohort

We evaluated the associations between glycemic therapies and prevalence of diabetic peripheral neuropathy (DPN) at baseline among participants in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial on medical and revascularization therapies for coronary artery disease (CAD) and on insulin-sensitizing vs. insulin-providing treatments for diabetes. A total of 2,368 patients with type 2 diabetes and CAD was evaluated. DPN was defined as clinical examination score > 2 using the Michigan Neuropathy Screening Instrument (MNSI). DPN odds ratios across different groups of glycemic therapy were evaluated by multiple logistic regression adjusted for multiple covariates including age, sex, hemoglobin A1c (HbA1c), and diabetes duration. Fifty-one percent of BARI 2D subjects with valid baseline characteristics and MNSI scores had DPN. After adjusting for all variables, use of insulin was significantly associated with DPN (OR = 1.57, 95% CI: 1.15-2.13). Patients on sulfonylurea (SU) or combination of SU/metformin (Met)/thiazolidinediones (TZD) had marginally higher rates of DPN than the Met/TZD group. This cross-sectional study in a cohort of patients with type 2 diabetes and CAD showed association of insulin use with higher DPN prevalence, independent of disease duration, glycemic control, and other characteristics. The causality between a glycemic control strategy and DPN cannot be evaluated in this cross-sectional study, but continued assessment of DPN and randomized therapies in BARI 2D trial may provide further explanations on the development of DPN.

Correlation between macular and retinal nerve fibre layer Fourier-domain OCT measurements and visual field loss in chiasmal compression

Purpose The aim of this study was to test the correlation between Fourier-domain (FD) optical coherence tomography (OCT) macular and retinal nerve fibre layer (RNFL) thickness and visual field (VF) loss on standard automated perimetry (SAP) in chiasmal compression. Methods A total of 35 eyes with permanent temporal VF defects and 35 controls underwent SAP and FD-OCT (3D OCT-1000; Topcon Corp.) examinations. Macular thickness measurements were averaged for the central area and for each quadrant and half of that area, whereas RNFL thickness was determined for six sectors around the optic disc. VF loss was estimated in six sectors of the VF and in the central 16 test points in the VF. The correlation between VF loss and OCT measurements was tested with Spearman`s correlation coefficients and with linear regression analysis. Results Macular and RNFL thickness parameters correlated strongly with SAP VF loss. Correlations were generally stronger between VF loss and quadrantic or hemianopic macular thickness than with sectoral RNFL thickness. For the macular parameters, we observed the strongest correlation between macular thickness in the inferonasal quadrant and VF loss in the superior temporal central quadrant (rho=0.78; P<0.001) whereas for the RNFL parameters the strongest correlation was observed between the superonasal optic disc sector and the central temporal VF defect (rho=0.60; P<0.001).