Blepharospasm in Japan: A Clinical Observational Study From a Large Referral Hospital in Tokyo.

Focal dystonia is regarded as a characteristic feature of blepharospasm. However, patients do not always present with motor symptoms. To clarify the clinical features of blepharospasm in Japan, we conducted a retrospective observational study involving a large population of patients from a single institution. Common symptoms included difficulty opening the eyes, photophobia, and ocular pain/irritation. Initial symptoms often occurred following the long-term use of psychotropics such as etizoram, benzodiazepines, and zolpidem (32% of patients). Our findings demonstrated that the clinical presentation of blepharospasm is heterogenous, and that understanding regarding sensory-dominant forms of the disease may be poor among practitioners in Japan.

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.

Immunocytochemical characteristics of Müller cells cultured from adult rabbit retina.

The antigenic expression of glial fibrillary acidic protein (GFAP), vimentin, S-100 protein and neurofilament triplex polypeptide was examined in cultured glial (Müller) cells from adult rabbit retina using immunocytochemical techniques. Most of the cultured cells were labelled with carbonic anhydrase C which has been considered to be the most specific marker of Müller cells. Most of the cultured cells were also positive for GFAP, a result which differs from previous observations on whole retina. Using a double labelling technique, 70-90% of cultured cells showed positive labelling for GFAP and vimentin although the staining intensity was stronger in the case of the latter. Fifty to seventy percent of cultured cells showed positive immunofluorescence to S-100 protein. Immunoelectron microscopy confirmed that GFAP and vimentin were localised along the intermediate glial filaments. S-100 protein was present in both the cytoplasm and the nucleoplasm of the majority of cells, but surprisingly in approximately 30% of cells the nucleoplasm was not labelled, a result which again is different from previously reported studies on whole retina. Neurofilament triplex polypeptide was not identified either by immunofluorescence or by immunoelectron microscopy. The results indicate that Müller cells in culture show a different antigenic expression to similar cells in whole retina.

Quantitative determination of heteroplasmy in Leber's hereditary optic neuropathy by single-strand conformation polymorphism.

PURPOSE: The maternal inheritance of Leber's hereditary optic neuropathy (LHON) is caused by defects in the genes of mitochondrial DNA (mtDNA). The most prevalent mtDNA mutation, present in 40% to 90% of families with this disease, is a G to A substitution at nucleotide position 11778. The rapid and accurate quantification of heteroplasmy of this mutation will help determine the relative risk for disease expression. METHODS: The authors conducted screening tests for heteroplasmy in 44 visually affected patients with the 11778 mutation and 34 unaffected members of 36 Japanese families with LHON using the single-strand conformation polymorphism analysis. This method can detect even a single base difference between the sequences of wild type and mutant DNA strands. The percentage of mutant mtDNA was calculated using an image analyzer. RESULTS: Single-strand conformation polymorphism analysis allowed the detection of heteroplasmy ranging from 5% to 95%. Five (14%) of the 36 families showed heteroplasmy, and 14 (18%) of the 78 persons tested had heteroplasmy ranging from 10% to 94%. Seven patients with heteroplasmy with visual loss had mutant mtDNA ranging from 62% to 94%. CONCLUSIONS: Single-strand conformation polymorphism analysis is rapid, efficient, and accurate for detecting point mutations and quantifying heteroplasmy in mtDNA. Individuals with heteroplasmy with less than 60% of mutant mtDNA in circulating leukocytes are probably at lesser risk for developing optic atrophy.

Evidence for preserved direct pupillary light response in Leber's hereditary optic neuropathy.

AIMS/BACKGROUND: Pupillary light response is usually defective in all types of optic neuropathy. However, the authors have observed in patients with Leber's hereditary optic neuropathy (LHON) relatively normal light response, with consequent misdiagnosis psychogenic visual loss in some cases. To confirm this clinical impression, afferent pupillary defect was assessed by measurement of adjusted constriction amplitude (CA) and escape rate (ER) by infrared videopupillography (Iriscorder-C 2515). METHODS: Thirteen consecutive patients (26 eyes) with LHON (average age 27.2 years) were examined; 12 had the mitochondrial DNA 11778 mutation and one the 14484 mutation. Seven of these patients had a positive family history. For comparison, the above rates were determined in 19 patients (23 eyes) with idiopathic optic neuritis (ON; average age 35.1 years), 18 patients (19 eyes) with anterior ischaemic optic neuropathy (AION; average age 58.1 years), and 25 volunteers (50 eyes) with healthy eyes (average age 39.6 years). RESULTS: The distribution of visual acuity was essentially the same in all optic neuropathy groups. Reduction in CA and increase in ER were significant in patients with ON and AION, but not in those with LHON. Only slight afferent pupillary defect was evident even 2 years after the onset of LHON. CA in AION and ER in ON were correlated statistically with visual acuity and Humphrey mean threshold deviation, while CA and ER in LHON were not. CONCLUSION: Pupillary light response in patients with LHON obviously differs from that in patients with other types of optic neuropathy. LHON appears to be pathophysiologically characterised by well preserved afferent fibres for pupillary light response (probably from W cells). Besides being of pathogenetic interest, the detection of clinical features should facilitate the diagnosis of LHON particularly when family history provides no indication.

Cytosolic calcium transient increase through the AMPA/kainate receptor in cultured Müller cells.

The intracellular concentration of free calcium ions ([Ca2+]i) following administration of glutamate agonist was monitored for retinal Müller cells cultured from adult rabbits using a fluorescence microscope equipped with a video camera system. The calcium concentration was imaged with fura-2. The transient increase of [Ca2+]i was observed following the administration of L-glutamate (3 mM), kainate (0.07-7 mM) and L-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA, 0.07-7 mM), but not N-methyl-L-aspartate (NMDA, 0.7-7 mM) in Mg(2+)-free medium. The AMPA/kainate-induced increase of [Ca2+]i was blocked by the non-NMDA glutamate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) or low concentrations of external calcium. High K+ solution induced a slight but definite increase in [Ca2+]i which was blocked by nifedipine, a voltage-dependent calcium channel blocker, at 100 microM, suggesting that L-type calcium channels are present in cultured Müller cells. The AMPA-induced transient increase of [Ca2+]i was not blocked at the same concentration of nifedipine. There must be an influx of calcium ions through non-NMDA AMPA-kainate receptors in Müller cells. In the retina, glutamate receptor-linked events are no longer considered as specific to neurons.

Central serous chorioretinopathy complicating systemic corticosteroid treatment.

Central serous chorioretinopathy developed in 2 cases of retrobulbar neuritis during systemic treatment with corticosteroids. Fluorescein angiography confirmed leakage surrounded by central serous detachment of the retina. In one case the central serous chorioretinopathy recurred 3 times during 3 separate courses of treatment. Spontaneous recovery accompanied a reduction in steroid treatment to a low level. It is suggested that high dosage corticosteroids may damage the posterior blood-ocular barrier.

Spectrum of pathogenic mitochondrial DNA mutations and clinical features in Japanese families with Leber's hereditary optic neuropathy.

PURPOSE: To investigate the incidence and clinical significance of primary or proposed secondary mitochondrial DNA (mtDNA) mutations in Japanese patients with Leber's hereditary optic neuropathy (LHON). METHODS: Blood samples from the 80 unrelated Japanese patients with bilateral optic atrophy were screened for primary LHON mutations. Patients found to have a primary LHON mutation were then tested for 9 proposed secondary LHON mutations. We investigated the association between these mutations and clinical characteristics. RESULTS: Primary mtDNA mutations were identified in 68 patients: at np 3460 in 3 (4%) of 68 patients, at np 11,778 in 59 patients (87%), and at np 14,484 in 6 patients (9%). We identified 5 secondary mtDNA mutations (at np 3394, 4216, 7444, 9438 or 13,708) in 10 (15%) of 68 LHON patients and 3 mutations (at np 3394, 4216 or 3708) in 6 (7%) of 90 healthy Japanese individuals. No patient was positive for more than one secondary mutation. The frequency of secondary mutations was similar in the 68 LHON patients and 90 controls. The clinical features of the Japanese patients with any of the 3 primary LHON mutations were similar to those of Caucasian patients, despite different mtDNA backgrounds in these populations. The percentage of patients with familial LHON harboring the 3460 or 14,484 mutations was lower in the Japanese population. CONCLUSIONS: Japanese patients with LHON exhibited a very high incidence (87%) of the 11,778 primary mutation. Most of the proposed secondary LHON mutations were rare in the Japanese population and they, except the 7444 mutation, may not influence the clinical features of LHON.

Malignant schwannoma of the heart.

Primary cardiac tumor is an extremely rare disease entity. Only three cases of primary malignant cardiac schwannoma, the subject of this report, have been recorded in Japan. Recently, we encountered a case of malignant schwannoma in which retention of pericardial effusion was the first clinical finding. This case was a 30-year-old female, who had dyspnea at work, general fatigue, and fever. Striking cardiac expansion was seen, with a cardiothoracic ratio (CTR) of 69% on chest x-ray. Two-dimensional echocardiograms showed a large volume of pericardial effusion between the side wall of the left ventricle and the epicardium, and the presence of a parenchymatous tumor. An increase in tumor size was detected on chest computer tomography (CT) scan. Using a pump oxygenator, median sternotomy was performed to reach the epicardium. A pale yellow, soft tumor was seen in the left atrium near the left ventricle. Histologically, the patient was diagnosed as having a malignant schwannoma. We have reported a case of primary malignant schwannoma which was surmised to have arisen from the boundary between the atrium and the ventricle.

Evaluation of viral myocarditis in children by radionuclide method.

Evaluation of viral myocarditis is essential for the clinician to assess the prognosis. In this study, Tl-201 myocardial scintigraphy and Tc-99m gated cardiac blood pool scan were performed in 16 patients with myocarditis diagnosed by clinical symptoms and laboratory findings and these nuclear medicine techniques were followed up for 5 years. Exercise Tl-201 scintigraphy using a bicycle ergometer was performed in 8 patients by SPECT imaging. There were mild to severe persistent defects found in all cases (100%), but pressure rate products showed normal response. The Tl-201 defect ratio improved gradually, but did not change significantly. In the resting Tl-201 image one of 16 patients showed severe multifocal defects. LVEF increased significantly from 1 year to 5 years after onset, while RVEF measured by gated blood pool scans showed slight increases 3 years to 5 years after diagnosis. It was concluded that myocardial perfusion improved only incompletely. Cardiac function (LVEF and RVEF) improved gradually, and pressure rate products were normal. Myocarditis should therefore be followed up in order to assess the prognosis; moreover, the relationship of myocarditis to dilated cardiomyopathy needs to be further studied.

Scanning electron microscopy of retinal ganglion cells by applying D,L-2-aminoadipic acid.

Retinal ganglion cells of the cat were clearly demonstrated in scanning electron microscopy. For identification of the cells, D,L-2-aminoadipic acid, a gliotoxic compound, was applied. Müller cells as well as astrocytes were destroyed by intravitreal injection of the aminoadipic acid prior to the enucleation. Balloon-shaped retinal ganglion cells with an axonal process were visualized in the normal cat retina. Flattened and sometimes indented ganglion cells were observed in the pathologic retina which was made 2 weeks after optic nerve transection. Pretreatment with the aminoadipic acid was a very effective method for the identification of the retinal ganglion cells by scanning electron microscopy.

Ultrastructural study on centrifugal fibers in the feline retina.

Morphological studies were carried out to elucidate whether centrifugal fibers are present in the cat retina. Unilateral optic nerve transection with the minimum vascular damage was performed at 6 mm behind the eyeball via the soft palate approach in adult specific pathogen free cats. Light and electron microscopic observations were performed at 40 and 96 hours after the optic nerve transection. At 40 hours, when there was no evidence of degenerative change in the retinal ganglion cells, degenerative changes were observed in the neuronal processes in the outer part of the inner plexiform layer. Two forms of degeneration occurred in close proximity to the cell bodies or the processes of amacrine cells: electron opaque and electron lucent degeneration. Since degeneration of the ganglion cells became manifest at 96 hours, the early neuronal changes in the inner plexiform layer were thought to represent degeneration of the centrifugal fibers.

P1-/P2-purinergic receptors on cultured rabbit retinal Müller cells.

Adenosine 5'-triphosphate (ATP) and its metabolic products function as neurotransmitters or neuromodulators under the control of P1/P2-purinergic receptors. To determine the presence of these receptors on retinal Müller cells, spectrofluorometry was carried out on intracellular calcium mobilization, using Fura-2 images. Müller cells were cultured from adult rabbit retinas. Cytosolic calcium ([Ca2+]i) increased dose dependently with the application of ATP. This response was not blocked when a calcium channel blocker, nifedipine, was present, but this response was blocked, for the most part, when a P2 receptor antagonist, pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS) was present. Increase in [Ca2+]i was noted by the A1 or A2 agonist, which was blocked completely by each antagonist. Response to the A1 agonist was apparent only at high concentrations. Increase in [Ca2+]i was seen in some cells following administration of the P2x agonist, methylene ATP, only at a high concentration (100 microM) but not in the presence of PPADS (50 nM). The greatest increase in [Ca2+]i was induced by a P2y agonist, methyl thio ATP at 1 to 10 microM, which was completely blocked by PPADS. Cultured Müller cells are thus shown quite likely to possess the P1-/P2-purinergic receptors including A2 and P2y.

Cerebello-oculo-hepato-renal syndrome with possible mitochondrial dysfunction.

Bilateral retinal dysfunction with optic atrophy was evident in a 26-year-old man along with renal, hepatic and cardiac dysfunction. MRI showed undersized cerebellar vermis. Blood lactate and pyruvate were high, indicating possible mitochondrial dysfunction. In biopsied biceps muscle, some ragged red fibers were identified. In five usually congenital or inherited syndromes, Dandy-Walker, Joubert, Arima, Dekaban and COACH, the symptoms such as hypoplasia or aplasia of the cerebellar vermis with multiple ocular and systemic disorders serve as the basis for differential diagnosis. The present case showed numerous symptomatic similarities and a few specific differences with Arima, Dekaban and COACH syndromes. These three syndromes and the present case were thus given a single designation, cerebello-oculo-hepato-renal syndrome, although the present case was an adult patient with sporadic onset. Some systemic disorders not included in cerebello-oculo-hepato-renal syndrome were also noted in our case and may possibly be explained by mitochondrial dysfunction, as indicated by blood pyruvate and lactate levels and the presence of ragged red fibers in biopsied biceps muscle. The relationship between cerebello-oculo-hepato-renal syndromes and mitochondrial dysfunction is discussed.

Possible roles of AMPA/KA receptor in cultured Müller cells.

In order to identify the function of the AMPA/KA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate/kainate) receptor in cultured Müller cells, we studied the difference in the affinity of this receptor for cultured Müller cells and retinal neurons (neurons), comparing these to the characteristics of cultured Müller cells exposed to kainate (KA), a neurotoxic amino acid. The difference in the cellular responses of Müller cells and neurons to AMPA was evaluated by measuring the rapid change in intracellular calcium ions. Results showed that neurons were more sensitive to AMPA than Müller cells; the percentage of cells responding to AMPA was always higher for neurons. When Müller cells were exposed to 0.5 mM KA, the morphology of the cells was not affected and the concentration of lactate dehydrogenase in the culture solution did not increase. However, the percentage of cells responding to a high concentration of AMPA was higher in the Müller cells exposed to KA than in those not exposed. These findings indicated that the affinity of the AMPA receptor was lower in Müller cells than in neurons, and that Müller cells were resistant to neurotoxic amino acids. It was also suggested that when an extremely large amount of neurotoxic amino acid was released into the retina as a result of ischemia, Müller cells actively protected the neurons.

Orthograde axonal transport of optic nerve and injury--morphological study.

To investigate the effects of injury to the orthograde axonal transport in the optic nerve, horseradish peroxidase (HRP) was injected into the vitreous of the cat eye after various types of optic nerve injury, and the retina and optic nerve were examined with light and electron microscopes 8 hours after the injection. The optic nerve was sectioned in one eye at about 6 mm behind the eyeball and the optic nerve of the contralateral eye was used as the control. HRP reaction products were frequently observed within the retinal ganglion cells and their axons of the nerve fiber layer as well as in the retrolaminar optic nerve on the experimental side, and the findings were similar to those on the control side. The optic nerve was injured by cryocoagulation for 10 seconds or 30 seconds, and ischemic changes of various degrees were induced. Intracellular and intra-axonal HRP reaction products were markedly reduced at the retrolaminar portion, and the degree of reduction depended on the duration of cryocoagulation. The section of the optic nerve had, at least in the early stage, only minimal effects on the orthograde axonal transport, but the optic nerve injury accompanied by ischemic changes markedly blocked the axonal transport in both the inner part of the retina and the optic nerve.

Junction scotoma and involvement of the optochiasmal junction.

In two patients, ipsilateral central scotoma and contralateral superior temporal hemianopic field defect indicated involvement of the junction of the optic nerve and chiasm, the optochiasmal junction. In both cases, computed tomography and carotid angiography confirmed mass lesions at this location. After surgical removal of a parasellar tumor in one case, we found that the optic nerve and the anterior part of the optic chiasm were compressed upwards. The previously reported examples of these perimetric findings are reviewed and compared with those of our cases. We concluded through this study that the characteristic combination of visual field defects, namely central or paracentral scotoma on the involved side and superior temporal field defect on the uninvolved side, should be termed junction scotoma.

Circadian rhythm of human electroretinogram.

In order to ascertain the presence of circadian rhythm in the electrical responses of the retina, scotopic electroretinogram (ERG) evoked mainly by light flash stimulus was recorded consecutively in 14 normal healthy subjects during a 24-hour period. The ERGs were measured at 6, 12, 18 and 24 o'clock. Both a- and b-waves were analyzed. The a-wave amplitude of all subjects studied showed no circadian rhythm. By our criteria, the b-wave amplitude showed circadian rhythm in 8 of the 14 subjects. The minimum amplitude of the b-wave was seen at 6 o'clock. The amplitude of the b-wave was significantly higher at 12 o'clock when compared with the amplitude at 6, 18 and 24 o'clock. This tendency was repeatedly observed. The presence of circadian rhythm in the scotopic b-wave was, therefore, suggested. This rhythm had a good correlation with the circadian rhythm of dopamine beta-hydroxylase in the serum and no correlation with the corticosteroid level in the serum. The possibility of circadian rhythm in the human ERG should be taken into consideration for routine clinical application.

Corticosteroid-induced central serous chorioretinopathy.

Five patients were identified by medical records and fluorescein angiography as having developed central serous chorioretinopathy (CSC) during corticosteroid treatment. These five and 28 previously reported corticosteroid-induced CSC occurrences were studied to clarify the differences between idiopathic CSC and corticosteroid-induced CSC. Nine previously reported occurrences of corticosteroid-induced multiple posterior pigment epitheliopathy (MPPE) were also reviewed. Corticosteroid-induced CSC patients were older and less male-dominant; in MPPE, female patients predominated and most had bilateral involvement. The onset of CSC was within 70 days of corticosteroid administration in the short latency group, and more than 6 months after administration in the prolonged latency group. Daily doses of prednisolone usually exceeded 20 mg in the short latency group and was less than 20 mg in the prolonged latency group. Immunosuppressive agents such as cyclophosphamide were related to a lower daily dose at onset.

Ultrastructural pleomorphism in medulloepithelioma of the ciliary body: a comparative study of tumour cells and fetal ciliary epithelium.

A locally aggressive nonteratoid intraocular medulloepithelioma occurring in a two-year-old boy was studied by electron microscopy. For comparison the primitive pars plana region was examined in human fetal eyes obtained at 16, 18 and 22 weeks of gestation. The tumour was polymorphic with neural, intermediate and epithelial components. The neural component of the tumour resembled the zonulae adherentes dominant cell junction seen in the apical part of the unpigmented epithelium at 16 weeks, while the well-developed junctional complexes and interdigitations seen in the unpigmented epithelium at 22 weeks resembled those in the epithelial component of the tumour. Intermediate cells which exhibited characteristics of both neural and epithelial components, particularly in the cell junctional features, were found. Pleomorphism in nonteratoid medulloepithelioma might be accounted for by the developmental stage at which the tumour is initiated.