Glucose hypermetabolism in the thalamus of patients with drug-induced blepharospasm.

We examined the difference in cerebral function alterations between drug-induced blepharospasm patients and essential blepharospasm (EB) patients by using positron emission tomography with (18)F-fluorodeoxyglucose. Cerebral glucose metabolism was examined in 21 patients with drug-induced blepharospasm (5 men and 16 women; mean age, 53.1 [range, 29-78] years), 21 essential EB patients (5 men and 16 women; mean age, 53.0 [range, 33-72] years) and 24 healthy subjects (6 men and 18 women; mean age, 57.9 [range, 22-78] years) with long-term history of benzodiazepines use (drug healthy subjects). Drug-induced blepharospasm patients developed symptoms while taking benzodiazepines or thienodiazepines. Sixty-three normal volunteers (15 men and 48 women; mean age, 53.6 [range, 20-70] years) were examined as controls. Differences between the patient groups and control group were examined by statistical parametric mapping. Additionally, we defined regions of interests on both sides of the thalamus, caudate nucleus, anterior putamen, posterior putamen and primary somatosensory area. The differences between groups were tested using two-sample t-tests with Bonferroni correction for multiple comparisons. Cerebral glucose hypermetabolism on both side of the thalamus was detected in drug-induced blepharospasm, EB patients and drug healthy subjects by statistical parametric mapping. In the analysis of regions of interest, glucose metabolism in both sides of the thalamus in the drug-induced blepharospasm group was significantly lower than that in the EB group. Moreover, we observed glucose hypermetabolism in the anterior and posterior putamen bilaterally in EB group but not in drug-induced blepharospasm group and drug healthy subjects. Long-term regimens of benzodiazepines or thienodiazepines may cause down-regulation of benzodiazepine receptors in the brain. We suggest that the functional brain alteration in drug-induced blepharospasm patients is similar to that in EB patients, and that alteration of the GABAergic system might be related to the pathology of both blepharospasm types.

Decreased dopamine D receptor binding in essential blepharospasm.

OBJECTIVES: The purpose of this study was to investigate whether dopamine D(2) receptor binding was altered in the striatum of essential blepharospasm patients. METHODS: Striatal dopamine D(2) receptor binding was measured with positron emission tomography and [(11)C]raclopride. We studied eight drug-naive patients with bilateral blepharospasm and eight age-matched normal controls. RESULTS: The uptake indices in the blepharospasm group were significantly reduced by 11.7% in the caudate (P < 0.005), 11.6% in the anterior putamen (P < 0.0001), and 10.3% in the posterior putamen (P < 0.005) relative to the control group. CONCLUSIONS: This study indicates decreased dopamine D(2) receptor binding in the entire striatal region of blepharospasm patients. The findings suggest that decreased dopamine D(2) receptor binding might be one of the predisposing factors that leads to the dysfunction of the motor circuit, resulting in the loss of broad inhibition of unwanted movements during an intended movement in blepharospasm patients.

Development of myopia as a hazard for workers in pneumatic caissons.

BACKGROUND/AIM: Pneumatic caisson engineering has been developed for large civil engineering constructions. Because of complaints of blurred vision by personnel working in pneumatic caissons, the development of myopia was suspected. The aim of this study was to determine the cause of the blurred vision and the mechanism underlying the changes. METHODS: 12 caisson workers underwent a complete ophthalmological examination after completing up to 11 weeks of work (4 days/week) in a pneumatic caisson. Six months later, nine of the workers were examined again. RESULTS: Nine subjects were myopic at the initial examination, and seven of these were considered to have developed the myopia after starting to work in the pneumatic caisson. Six months after completion of the work, the mean refractive change was significantly towards hyperopia. CONCLUSIONS: The blurred vision in pneumatic caisson workers was in all likelihood due to the development of myopia. The refractive shift towards hyperopia after completion of work in the pneumatic caisson supports this and demonstrates that the changes were temporary. The myopia is similar to the myopia seen in patients treated by hyperbaric oxygen. Careful monitoring of the refraction of caisson workers should be performed for industrial health control.

Cortical blindness following aortic arch surgery.

PURPOSE: To report a patient with Marfan's syndrome in whom cortical blindness occurred after planned circulatory arrest during aortic arch surgery. CASE: A 31-year-old man underwent aortic arch surgery because of an acute aortic dissection due to Marfan's syndrome. He noticed poor vision after surgery, although his pupillary reflexes and fundi appeared normal. Magnetic resonance imaging (MRI) and positron emission tomography (PET) were performed 2 years and 9 months after his operation. RESULTS: The MRI revealed cortical atrophy in the occipital cortex, and PET scans with fluorodeoxy glucose revealed extreme glucose hypometabolism in the occipital cortex. The atrophy reflected cortical laminar necrosis that presumably occurred during the planned circulatory arrest to the brain during the surgery. CONCLUSION: It is occasionally difficult to diagnose cortical blindness with MRI, especially at the acute stage. We could find significant hypometabolism of the occipital cortex using PET.

Auditory triggered mental imagery of shape involves visual association areas in early blind humans.

Previous neuroimaging studies identified a large network of cortical areas involved in visual imagery in the human brain, which includes occipitotemporal and visual associative areas. Here we test whether the same processes can be elicited by tactile and auditory experiences in subjects who became blind early in life. Using positron emission tomography, regional cerebral blood flow was assessed in six right-handed early blind and six age-matched control volunteers during three conditions: resting state, passive listening to noise sounds, and mental imagery task (imagery of object shape) triggered by the sound of familiar objects. Activation foci were found in occipitotemporal and visual association areas, particularly in the left fusiform gyrus (Brodmann areas 19-37), during mental imagery of shape by both groups. Since shape imagery by early blind subjects does involve similar visual structures as controls at an adult age, it indicates their developmental crossmodal reorganization to allow perceptual representation in the absence of vision.

[Visual evoked potentials elicited by pseudorandom stimulation in macular degeneration].

PURPOSE: To investigate the effect of a central scotoma on the amplitude, latency, and temporal frequency characteristics(TFCs) of the visual evoked potentials(VEPs) elicited by a pseudorandom binary stimulus(PRBS). METHOD: Patients with age-related macular degeneration(AMD) were selected, and VEPs were recorded from 26 eyes with AMD(17 eyes with visual acuity of less than 0.2, and 9 eyes with visual acuity between 0.3 and 0.9). Nine eyes of age-matched normal volunteers served as controls. To acquire the PRBS-VEPs, one eye was stimulated with a PRBS stimulus. The first order kernel was calculated from a cross correlation between PRBS and VEPs. The Fourier transformed first-order kernel was used as the TFC of the VEPs. RESULTS: The P2 latency of the first order kernels was delayed(p < 0.05), and the P2-N2 amplitude was reduced(p < 0.01) in AMD. A depression of the TFC values in the 6-18 Hz band was prominent in the patients with AMD(p < 0.01). CONCLUSION: The TFC, were strongly correlated with the visual acuity of patients with macular degeneration.

Neuroreceptor bindings and synaptic activity in visual system of monocularly enucleated rat.

PURPOSE: To study the changes in the distribution of postsynaptic benzodiazepine (BDZ) and presynaptic adenosine A(1) (AA(1)) receptors in the superior colliculus (SC) and visual cortex (VC) of rats following monocular enucleation. METHODS: The right eyes of 6-week-old Long-Evans rats were enucleated and ex vivo autoradiography was performed on the SC and VC obtained at different times up to 8 weeks after the enucleation. [14C]deoxyglucose was used to detect glucose metabolism, and [11C]flumazenil and [1-methyl-(11)C]8-dicyclopropylmethyl-1-methyl-3-propylxanthine ([11C]MPDX) were used to map BDZ and AA(1) receptors, respectively. The receptor-specific binding for 11C was determined, and 11C and 14C activities were evaluated separately in the same tissue by a double tracing method. RESULTS: The uptake of [14C]deoxyglucose in the SC was depressed immediately after enucleation and gradually recovered. The binding of [11C]flumazenil to BDZ receptors in the contralateral SC was increased at week 2, and then returned to the pre-enucleation levels. The uptake of [11C]MPDX by the AA(1) receptors in the contralateral SC decreased by about 67% on day 5 after enucleation and remained low thereafter. In the contralateral VC, the uptake of [14C]deoxyglucose decreased immediately after the enucleation followed by a gradual recovery, whereas the uptake of [11C]flumazenil and [11C]MPDX was not altered. CONCLUSIONS: The axon degeneration related decrease of the AA(1) receptor density resulted in a transient up-regulation of postsynaptic BDZ receptor density in monocularly enucleated adult rats. These results suggest that these radioligands can be used to study the distribution of the postsynaptic BDZ and presynaptic AA(1) receptors in the visual system and can probably be applied to the human visual system for positron emission tomography.

Application of visual evoked potentials for preoperative estimation of visual function in eyes with dense cataract.

PURPOSE: To determine whether the temporal frequency characteristics of the visual system as determined by visually evoked potentials (VEP) can be used for a preoperative estimation of the visual function in eyes with cataracts. METHODS: Light stimuli driven by a pseudorandom binary sequence (PRBS) of 40950 ms duration were presented and EEG recordings were made from 13 control and 20 patients with cataracts preoperatively and 1 week after cataract operation. The first kernel of the PRBS-VEP was obtained as the first-order cross-correlation function between PRBS and PRBS-VEP. The Fourier transform of this function was used as the temporal frequency characteristic (TFC). RESULTS: The mean +/- standard deviation of the latency and amplitude of the VEP in normal controls were 110.8+/-4.3 ms and 2.01+/-0.67 microV, respectively. A high correlation (r>0.7) between the pre-and postoperative VEP waveform was obtained in 13 eyes (65%), and 14 eyes (70%) in the VEP-TFC curves. The sensitivity of the examination was 73%, 27%, and 91% for the latency, amplitude and TFC of the VEP, respectively. The specificity of the examination was 67%, 100%, and 89% for the same measures. Eleven of 12 eyes with abnormal TFC preoperatively showed retinal or optic nerve lesions postoperatively. False-negative results were seen in cases with delayed corneal edema. CONCLUSION: Postoperative visual function of patients with cataracts can be predicted by preoperative measurement of the TFC obtained by PRBS-VEP.

Clinicopathological report of retinitis pigmentosa with vitamin E deficiency caused by mutation of the alpha-tocopherol transfer protein gene.

PURPOSE: To discuss the clinicopathological findings in a patient with retinitis pigmentosa (RP) accompanied by a vitamin E deficiency caused by an H101Q mutation in the alpha-tocopherol transfer protein (alpha-TTP) gene. CASE: The clinical course of this patient was followed by conventional ophthalmological examinations over a 3-year period. After the patient died from pancreatic cancer, the eyes were obtained, and examined by light and electron microscopy. OBSERVATIONS: The patient complained of night blindness subsequent to adult-onset ataxia, although the ataxia was very mild. His visual acuity was 0.6 OU, and ophthalmoscopy revealed RP sine pigmento. Ring scotomas were detected, and the electroretinography, electro-oculography, and dark-adaptation were altered. Fluorescein angiography showed granular hyperfluorescence around the macula. No progression of the visual and neurological symptoms was observed during the 10 years he was taking oral vitamin E. Histopathological examination revealed the loss of the outer and inner segments of the photoreceptors in the area corresponding to the ring scotoma, as well as a disorganization and shortening of the outer segments in the peripheral retina. CONCLUSIONS: We conclude that the clinical and pathological findings in the eyes of this patient having RP with vitamin E deficiency caused by an H101Q mutation are similar to those of common autosomal recessive RP. However, special attention is required in making a diagnosis of RP with vitamin E deficiency because RP with vitamin E deficiency is medically treatable. The mild Friedreich-type ataxia accompanying the RP may be helpful in identifying this disease.

Carbon-11-labeled KF21213: a highly selective ligand for mapping CNS adenosine A(2A) receptors with positron emission tomography.

In vivo assessment of the adenosine A(2A) receptors localized in the striatum with positron emission tomography (PET) may offers us a new diagnostic tool for neurological disorders. We evaluated the potential of [7-methyl-(11)C](E)-8-(2,3-dimethyl-4-methoxystyryl)-1, 3,7-trimethylxanthine ([(11)C]KF21213) as a PET ligand for mapping adenosine A(2A) receptors in the central nervous system. KF21213 showed a high affinity for the adenosine A(2A) receptors in vitro (Ki = 3.0 nM) and a very low affinity for the A(1) receptors (Ki > 10,000 nM). In mice, the striatal uptake of [(11)C]KF21213 increased for the first 15 min and then gradually decreased, whereas the uptake in the reference regions such as the cortex and cerebellum rapidly decreased. The uptake ratio of striatum to cortex and striatum to cerebellum increased to 8.6 and 10.5, respectively, at 60 min postinjection. The striatal uptake was significantly blocked by co-injection of carrier KF21213 or each of three other A(2A) antagonists, but not by co-injection of A(1) antagonist. The specific uptake was not detected in the cortex or in the cerebellum. Ex vivo autoradiography and PET clearly visualized adenosine A(2A) receptors in the rat striatum. [(11)C]KF21213 was the most selective tracer for mapping adenosine A(2A) in the central nervous system by PET among the tracers proposed to date.

Evaluation of iodinated and brominated [11C]styrylxanthine derivatives as in vivo radioligands mapping adenosine A2A receptor in the central nervous system.

In vivo assessment of the adenosine A2A receptors localized in the striatum by PET or SPECT offers us a new diagnostic tool for neurological disorders. In the present study, we evaluated the potential of iodinated and brominated styrylxanthine derivatives labeled with 11C as an in vivo probe. [7-Methyl-11C]-(E)-3,7-dimethyl-8-(3-iodostyryl)-1-propargylxan thine ([11C]IS-DMPX) and [7-methyl-11C]-(E)-8-(3-bromostyryl)-3,7-dimethyl-1-propargylxa nthine ([11C]BS-DMPX) were prepared by the 11C-methylation of corresponding 7-demethyl derivatives. An in vitro membrane binding study showed a high affinity (Ki values) of the two ligands for A2A receptor: 8.9 nM for IS-DMPX and 7.7 nM for BS-DMPX, and a high A2A/A1 selectivity: > 1100 for IS-DMPX and 300 for BS-DMPX. In mice, [11C]IS-DMPX and [11C]BS-DMPX were taken up slightly more in the striatum than in the reference regions such as the cortex and cerebellum. The uptake ratios of striatum to cortex and striatum to cerebellum gradually increased but were very small: 1.6-1.7 for the striatum-to-cortex ratio and 1.2 for the striatum-to-cerebellum ratio at 60 min postinjection. The uptake by these three regions was reduced by co-injection of an excess amount of carrier or an A2A antagonist KF17837, but not by an A1 antagonist KF15372. The blocking effects in the three regions were greater for [11C]BS-DMPX (32-57%) than for [11C]IS-DMPX (6-29%). Ex vivo autoradiography confirmed that the two ligands were slightly concentrated in the striatum. [11C]BS-DMPX showed more selective affinity for adenosine A2A receptors than [11C]IS-DMPX, but these results have shown that the two tracers were not suitable as in vivo ligands because of low selectivity for the striatal A2A receptors and a high nonspecific binding.

Bilateral serous retinal detachment associated with Alport's syndrome.

We report a 14-year-old girl with Alport's syndrome who developed bilateral exudative retinal detachment in the macula. With the development of chronic renal failure, bilateral serous retinal detachment appeared which had the retinal flecks characteristic of Alport's syndrome. The serous detachment was resolved and vision recovered following intensive hemodialysis. As far as we know this is the first case with documentation of the onset and resolution of serous retinal detachment in Alport's syndrome.

Benzodiazepine receptor distribution and cerebral blood flow in early blindness--a PET study.

We studied benzodiazepine receptor (BZR) distribution, which is thought to be affected by neuronal density in the cerebral cortex, and CBF using [11C]flumazenil and [15O]water PET in early blind (EB) and in blindfold sighted control (SC) subjects. PET images were co-registered to the subject's MRI. Using SPM96, MRI images were normalized in the Talairach and Tournoux coordinate system, and accordingly MRI-registered PET images were spatially normalized. Statistical parametric maps were computed on a voxel-by-voxel basis, using the general linear model. CBF for EB was significantly larger in the Brodmann area 17 and 18, especially anterior area, than that for SC, while there was no significant difference in BZR distribution. Our BZR data suggest that the amount of neurons do not change due to early visual deprivation in the visual cortex, in spite of high CBF in visual cortex of EB subjects.

Postmortem study of ataxia with retinitis pigmentosa by mutation of the alpha-tocopherol transfer protein gene.

A new syndrome of ataxia and retinitis pigmentosa with vitamin E deficiency caused by the missense mutation of alpha-tocopherol transfer protein (alpha-TTP) gene was recently proposed. After studying the first postmortem case with this mutation pathologically and biochemically, whether the symptoms can be treated by supplementation of vitamin E or not is discussed. The major pathological findings were retinal atrophy; severe dying back-type degeneration of the posterior column; and massive accumulation of lipofuscin in neurons including dorsal root ganglion (DRG) cells, which were almost identical to those in vitamin E deficient animals and patients with fat malabsorption. Also, mild loss of Purkinje cells was noted. Because robust expression of alpha-TTP was detected in the cerebellum as well as in the liver and the tissue concentration of vitamin E in the cerebellum was still low even after oral supplementation, the mild Purkinje cell loss might be related to the mutant alpha-TTP in the cerebellum. By contrast, in the DRG, thought to be mainly responsible for ataxia, no expression of alpha-TTP was detected, and the tissue concentration of vitamin E increased to normal after supplementation. It is therefore considered that oral supplementation of vitamin E should effectively counteract the progression of ataxia.

Cataract and retinal detachment in patients with severe atopic dermatitis who were withdrawn from the use of topical corticosteroid.

Many patients with severe atopic dermatitis (AD) in Japan are afflicted with persistent erythema of the face (atopic red face) that is not only resistant to topical corticosteroid, but often becomes worse with its use. During a three-year period (1991-1993), we treated 79 inpatients with severe AD by a combination of careful daily skin care, use of emollients, and exclusion of exacerbating factors. Occular complications before and after treatment were examined in these cases. After withdrawal of topical corticosteroid, almost all of the patients showed a temporary worsening of their skin condition. Immediately thereafter, their occular symptoms did not change. Cataract was found in 20 cases (25.3%), and retinal detachment in 9 (11.4%). After 2 months, 11 cases of cataract and 5 cases of retinal detachment in the peripheral retina were observed. However, these incidences were similar to the numbers reported in Japan during conventional treatment with topical corticosteroid. The development of cataract or retinal detachment had no relationship to serum IgE levels, personal history of respiratory atopy, the duration of topical corticosteroid use on the face, or treatment with systemic corticosteroid. Our observations suggest that patients who habitually tap or rub their faces strongly tend to develop cataract or retinal detachment at a statistically significant higher frequency. Patients with AD should have ophthalmologic examinations every one to two months for at least one year after a facial oozing attack or withdrawal of corticosteroid.

Multicenter clinical trial for evaluating methylprednisolone pulse treatment of idiopathic optic neuritis in Japan. Optic Neuritis Treatment Trial Multicenter Cooperative Research Group (ONMRG).

BACKGROUND: A randomized, controlled clinical trial was conducted in 1991 to compare an intravenous megadose of methylprednisolone with a control drug (mecobalamin) for treating acute idiopathic optic neuritis. CASES: Sixty-six cases from 22 clinical centers throughout Japan were examined to evaluate the treatment on visual function parameters, such as visual acuity, visual field, color vision, contrast sensitivity, and critical flicker frequency. OBSERVATIONS: The methylprednisolone pulse treatment group showed faster recovery of visual function, particularly the visual acuity at 1 week (P<.05), Humphrey field analyzer mean deviation at 3 weeks (P<.05), and color vision at 1 week (P<.05). Recovery of contrast sensitivity at several different spatial frequencies was significant in the pulse treatment group at 1 (P<.01), 2 (P<.05), and 4 weeks (P<.05) after the start of treatment. Visual function test results at 12 weeks and 1 year were essentially the same in the two treatment groups. Side effects appeared more frequently in the pulse treatment group than in the control (P<.05). CONCLUSIONS: Pulse treatment does not appear effective for idiopathic optic neuritis even though visual function in the pulse treatment group of this trial recovered more quickly during the initial phase compared to the controls. More effective and specific treatment should be established for optic neuritis.

Baseline features of idiopathic optic neuritis as determined by a multicenter treatment trial in Japan. Optic Neuritis Treatment Trial Multicenter Cooperative Research Group (ONMRG).

BACKGROUND: An optic neuritis treatment trial was conducted at 30 clinical centers in Japan using the same protocol. Patient participation was based on: age range of 14-55 years; acute symptoms indicative of unilateral optic neuritis of unknown or demyelinating origin; visual symptoms of 14-day duration or less; relative afferent pupillary defect in affected eye; and normal or swollen optic disc of affected eye. CASES: Initially, 102 patients qualified for participation; baseline data were obtained for analysis from 70 of these patients. Demographic characteristics of Japanese patients with optic neuritis were clarified and compared with those in a US study. OBSERVATIONS: The incidence of ocular or periocular pain and the presence of periventricular plaques were noted to be lower, and the incidence of disc swelling higher, in the Japanese patients, suggesting racial differences in the characteristics of the disease. Such differences may possibly be related to the lower incidence of multiple sclerosis in Japanese patients. The results of visual function tests were virtually the same in both studies. The nonaffected eyes of more than half the patients showed abnormal mean deviation in Humphrey field analysis, as also noted in the US study. CONCLUSIONS: The baseline clinical features of optic neuritis in the Japanese patients have been defined. Some racial differences in the characteristics of the disease may exist.

Visual temporal frequency characteristics determined by pseudorandom stimuli.

PURPOSE: To investigate whether a rapid and practical determination of the temporal frequency characteristic (TFC) of the visual system can be obtained by using the visually evoked potentials (VEPs) elicited by pseudorandom binary sequence (PRBS) stimulation. METHODS: VEPs were recorded from eight volunteers. For the conventional steady state VEPs (S-VEP), the eye was stimulated with five stimulus frequencies. To acquire the PRBS-VEPs, the eye was stimulated with a PRBS stimulus for 40 seconds. The TFC for the S-VEP was calculated from the root mean squared amplitude for each frequency using Fourier transform. For the PRBS stimulus, a cross-correlation function between PRBS (x[t]) and PRBS-VEP (y[t]) was calculated to obtain the TFC. RESULTS: The TFCs obtained by the PRBS and S-VEP methods were highly correlated (P < 0.05), and the TFC curves resembled those in the literature. Most important, the data necessary to determine the TFCs using the PRBS stimulus could be obtained in 4 minutes, whereas that for the S-VEP required 60 minutes for the two eyes. CONCLUSIONS: The high correlation between the TFCs obtained by the two methods indicated that the PRBS technique gives a good measure of the TFC of the human visual system. The significantly shorter time required for this method demonstrated that it is a practical method for determining the linear (and nonlinear) property of the visual system and that it may be useful in clinical applications.

Importance of fluorescein angiographic study in evaluating early retinal changes in Takayasu disease.

PURPOSE: To determine the usefulness of fluorescein angiography in studying Takayasu disease. METHODS: We examined 31 eyes in 16 patients with Takayasu disease using indirect ophthalmoscopy, color photography, and fluorescein angiography. Ophthalmoscopic and fluorescein angiographic findings were compared. RESULTS: Fluorescein angiography revealed no additional retinal changes in 10 eyes that had no retinal vein dilatation as seen by indirect ophthalmoscopy. Seven (33%) of 21 eyes that had dilated retinal veins also had additional abnormal findings, such as microaneurysms, arteriovenous shunts, retinal neovascularization, and avascular areas. Some differences in grading the stages of retinopathy were noted with these newly found retinal changes, as compared with the classifications determined by ophthalmoscopy alone. CONCLUSIONS: In Takayasu disease, studying the fundus of patients with fluorescein angiography is particularly important in correctly classifying the stages of retinopathy when the retinal vein appears dilated in ophthalmoscopic observation.

A family with Leber's hereditary optic neuropathy with mitochondrial DNA heteroplasmy related to disease expression.

A Japanese family has members with Leber's hereditary optic neuropathy resulting from the heteroplasmic 11778 mutation and the homoplasmic 4216 mutation. Quantitative determination of heteroplasmy was performed by a combination of polymerase chain reaction and single-strand conformation polymorphism analysis. The association between heteroplasmy and clinical features was determined. Eleven people from the maternal side of the family, including four affected and seven unaffected members, showed heteroplasmy of the mtDNA mutation ranging from 5% to more than 95%. Four possibly affected patients had more than 90% of the mutant mtDNA. Seven unaffected people had mutant mtDNA ranging from 5% to 77%. A recovery episode of visual acuity was noted in the history of three of the four patients. Heteroplasmy is likely to be a factor in the expression of disease in this family.