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.

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.

Adverse periocular reactions to five types of prostaglandin analogs.

PURPOSE: We investigated the appearance frequency of eyelid pigmentation and eyelash bristles after the use of five types of prostaglandin (PG) analogs. METHODS: This study included 250 eyes from 250 patients diagnosed with primary open-angle glaucoma or ocular hypertension who were treated with either latanoprost, travoprost, tafluprost, bimatoprost, or isopropyl unoprostone for >3 months in only one eye. Photographs of both eyes were obtained, and the images were assessed by three ophthalmologists who were masked to treatment type. The existence of eyelid pigmentation and eyelash bristles was judged, and images of the left and right eyes were compared. Subjective symptoms regarding the existence of eyelid pigmentation and eyelash bristles were investigated through a questionnaire. RESULTS: There was no significant difference between the five types of medications with regard to eyelid pigmentation (P=0.537). Use of isopropyl unoprostone resulted in a significantly lower incidence of eyelash bristles (P<0.0001). The questionnaire investigation showed that eyelid pigmentation and eyelash bristles were significantly more frequent with travoprost (42.0% and 42.0%, respectively) and bimatoprost (58.0% and 60.0%, respectively) than with other three medications (P<0.0001). CONCLUSION: The appearance frequency of eyelid pigmentation was similar among the five types of PG analogs studied, and eyelash bristles appeared less frequently with isopropyl unoprostone use. Patients are conscious of eyelash bristles; therefore, these adverse effects should be sufficiently explained to patients before PG administration.

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.

[Experimental approaches to prophylactic neuroprotective treatment for retinal and optic nerve disorders].

Neuroprotective treatment is increasingly recommended as a novel intervention for ischemic or degenerative disorders in the retina and optic nerve. To determine prophylactic neuroprotective action and the mechanism of various agents against N-methyl-D-aspartate NMDA- or L-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-induced cell death, in vitro experiments were conducted on retinal neurons and Müller cells. The effects of a calcium channel blocker, diltiazem, and a dopamine precursor, L-dopa, on glutamate agonist exposure were investigated using the TdT-mediated dUTP-biotin nick end labelling (TUNEL) method and comet assay. Prior administration of either one of the above two agents showed that cell death was prevented following exposure to NMDA or AMPA. Isolated administration of L-dopa at a concentration of 10(-4) M facilitates cell death, probably because of nitric oxide (NO) production. L-dopa concentrations of less than 10(-6) M did not result in increased cell death, and glutamate agonist-induced cell death was significantly suppressed by prior treatment at these low concentrations. Similar induction and suppression of cell death was also shown in cultured Müller cells. Based on our experiments and other published literature, we looked at three hypotheses for possible mechanisms for the neuroprotection of L-dopa, i.e., interactions with dopamine receptors, the anti-apoptotic action of NO, and the actions of neurotrophic or nerve growth factors. Neuroprotection appeared to occur through the D1 or D2 receptors. From data obtained from video-enhanced microscopic recordings, which can be used to observe real-time intracellular movement of particles, the movement after administration of a D1 receptor agonist was found to be remarkably different than that seen after D2 agonist administration. It is suggested that the action of dopamine on retinal cell death should be analyzed separately with respect to D1 and D2 receptors. We also discuss clinical application of these two agents in retinal and optic nerve ischemia.

Stromal keratitis and anterior uveitis due to herpes simplex virus-2 in a young child.

BACKGROUND: An uncommon case of stromal keratitis and anterior uveitis due to herpes simplex virus type 2 (HSV-2) is reported. CASE: The patient was a 3-year-old boy admitted for conjunctival injection of the right eye of unknown cause, accompanied by corneal opacity and anterior uveitis. OBSERVATIONS: High titers of antibodies against HSV and Epstein-Barr virus (EBV) were found in blood samples. Polymerase chain reaction (PCR) for the detection of HSV-1, -2, and EBV genome fragments was carried out using an anterior chamber sample as a template. An HSV-2 genome fragment was amplified by PCR. Administration of acyclovir and betamethasone was started, with the consequent elimination of corneal opacity, inflammatory cells, and keratic precipitates. CONCLUSION: PCR clearly showed that HSV-2 was the causative pathogen of the stromal keratitis and anterior uveitis in this young patient. Systemic EVB infection may induce systemic immunocompromised conditions that can lead to reactivation of HSV-2 followed by ocular disorders.

Do idebenone and vitamin therapy shorten the time to achieve visual recovery in Leber hereditary optic neuropathy?

OBJECTIVES: The authors investigated the effectiveness of idebenone combined with vitamin B2 and vitamin C in the treatment of patients with Leber hereditary optic neuropathy (LHON) in an early stage as compared with untreated patients with LHON. These agents may stimulate the formation of ATP. MATERIALS AND METHODS: For this retrospective study, the authors selected 28 outpatients with LHON from the Keio University Hospital. These patients were followed for 2 to 19 years from disease onset. They were divided into two groups: 14 untreated patients (11778 mutation in 10 patients, 3460 mutation in 2 patients, and 14484 mutation in 2 two patients); and 14 treated patients (11778 mutation in 11 patients, 3460 mutation in 1 patient, and 14484 mutation in 2 patients). The treated patients were administered medical treatment with idebenone, vitamin B2, and vitamin C for at least 1 year. The current study evaluated the following: 1) number of eyes with visual recovery > or = 0.3; 2) interval between the onset of LHON and the beginning of visual recovery; 3) interval between the onset of LHON and visual recovery to 0.3; and 4) interval between the beginning of medical treatment and the beginning of visual recovery in the treated subjects. RESULTS: There was no significant difference in the number of eyes with visual recovery > or = 0.3 in the two groups with the 3460, 11778, or 14484 mutation. Patients with visual recovery showed a fenestrated scotoma or a clearing of central vision. The mean interval between the onset of LHON and the beginning of visual recovery was significantly shorter in the treated group (11.1 months) than in the untreated group (17.4 months) (P = 0.03). The mean interval between the onset of LHON and visual recovery to 0.3 was significantly shorter in the treated group (17.6 months) than in the untreated group (34.4 months) (P = 0.01). The mean interval between the initiation of medical treatment to the beginning of visual recovery was 5.4 months. CONCLUSIONS: Results suggest that the administration of idebenone, vitamin B2, and vitamin C sped the recovery of vision in patients with LHON.

Corneal amyloidosis complicated by trichiasis. Immunohistochemical identification of the amyloid light chain protein

Purpose: To identify the amyloid protein of the corneal amyloidosis complicated by trichiasis.Methods: The two patients were 41-year-old and 38-year-old women with trichiasis. They had gelatinous drop-like corneal change in the hemilateral eye. The lesion was excised and examined by light and electron microscopy. Additionally, we performed an immunohistochemical study with immunofluorescence techniques using cryosections.Results: The amyloid deposits were confirmed with light and electron microscopy. Congo red positive staining was not reduced following pretreatment with potassium permanganate. Immunohistochemically, amyloid deposits in the cornea stained positively with serum human light chain kappa and lambda. Pretreatment of the section with 0.05% Tween-20 did not decrease the staining with fluorescence. The deposits stained negatively with serum prealbumin and keratin antibodies.Conclusions: These findings indicate the protein of the corneal amyloidosis complicating trichiasis to be an amyloid light chain (AL) protein that has never been identified in this kind of corneal amyloidosis.

[Corneal amyloidosis complicated by trichiasis--immunohistochemical identification of the amyloid light chain protein].

PURPOSE: To identify the amyloid protein of the corneal amyloidosis complicated by trichiasis. METHODS: The two patients were 41-year-old and 38-year-old women with trichiasis. They had gelatinous drop-like corneal change in hemilateral eye. The lesion was excised and examined by light and electron microscopy. Additionally, we performed an immunohistochemical study with immunofluorescence techniques using cryosections. RESULTS: The amyloid deposits were confirmed with light and electron microscopy. Congo red positive staining was not reduced following pretreatment with potassium permanganate. Immunohistochemically, amyloid deposits in the cornea stained positively with serum human light chain kappa and lambda. Pretreatment of the section with 0.05% Tween-20 did not decrease the staining with fluorescence. The deposits stained negatively with serum prealbumin and keratin antibodies. CONCLUSIONS: These findings indicate the protein of the corneal amyloidosis complicating trichiasis to be an amyloid light chain (AL) protein that has never been identified in this kind of corneal amyloidosis.

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.

Rapid increase in cytosolic calcium ion concentration mediated by acetylcholine receptors in cultured retinal neurons and Müller cells.

PURPOSE: This study was conducted to detect the presence of muscarinic or nicotinic receptors in cultured retinal neurons and Müller cells. METHODS: Pure Müller cell cultures and cocultures of retinal neurons and Müller cells were used; the former, obtained from adult rabbit retinas, and the latter, retinal neurons from neonatal rats, were cocultured with Müller cells. Intracellular calcium ion concentration ([Ca2+]i) following the administration of acetylcholine, a cholinesterase inhibitor (trichlorfon), nicotine or muscarinic agonist with or without a receptor antagonist was monitored using the calcium ion indicator, fura-2. RESULTS: Acetylcholine and trichlorfon induced rapid increase in [Ca2+]i in half of either cell type. Trichlorfon induced positive response in coculture but not in the pure Müller cell cultures. This positive response was blocked only partially in the presence of atropine. Approximately 30-40% of neurons responded to nicotine at 5 microM, which was significantly blocked by alpha-bungarotoxin at 50 nM. No response to nicotine could be detected in Müller cells. Approximately 50% of neurons responded to muscarine at 50 microM, but 500 microM was required for the formation of calcium transients in 50% of Müller cells. The muscarine inducement of rapid increase in [Ca2+]i was blocked by atropine. The agonist of M1 (a muscarinic receptor subtype), McN-A-343, at 0.5 microM induced the most significant and rapid increase in [Ca2+]i both in neurons and Müller cells. McN-A-343 administration at 0.05 microM induced positive response in half the neurons, but only in approximately 10% of Müller cells. Such positive response was not observed following preincubation with the M1 antagonist, pirenzepine, at 50 microM. CONCLUSIONS: Cocultured retinal neurons enhance the release of acetylcholine following anticholinesterase administration, and approximately half the neurons were found to possess muscarinic and nicotinic receptors. However, Müller cells appeared to possess only the less sensitive muscarinic receptor. Muscarinic receptor subtypes on either type of cell contained at least M1.

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.

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.

[Orbital and stomach metastasis from invasive lobular breast carcinoma].

Orbital or ocular metastatic tumors may originate from breast cancer. Few studies have been made regarding their histopathological classification. A 71-year-old female noted a tumor in the right orbital region. She had had bilateral breast cancer 2 years before and gastric cancer 5 months before. Histopathology had shown stage II invasive ductal cancer (scirrhus) in the right breast and stage III invasive lobular cancer in the left. Signet-ring cells were present in the breast and gastric cancers. Biopsy of the right lower eyelid showed poorly differentiated adenocarcinoma with signet-ring cells. Indian file pattern, which is specific for invasive lobular cancer, was also present, suggesting that the orbital tumor had metastatized from the left breast cancer. Genetic analysis of the gastric cancer using polymerase chain reaction showed a mutation at exon 8 of the p53 tumor suppressor gene, indicating the cancer to be metastatic. These results led to the conclusion that invasive lobular cancer of the left breast was the primary lesion for the gastric and orbital metastases. This case also illustrates that signet-ring cells, which are usually seen in gastric cancer, may be present in invasive lobular breast cancer and in orbital metastasis.

High incidence of visual recovery among four Japanese patients with Leber's hereditary optic neuropathy with the 14484 mutation.

The 14484 mutation in the ND6 gene of mitochondrial DNA (mtDNA) is a genetic mutation associated with Leber's hereditary optic neuropathy (LHON) in Caucasian patients who show a high incidence of visual recovery. We evaluated four Japanese patients with LHON associated with the 14484 mutation who were negative for eight proposed secondary mutations. There was no family history of optic atrophy in three of the four patients. All four patients were initially diagnosed as having optic neuritis, either anterior (Cases 1 and 3) or retrobulbar (Cases 2 and 4), based upon their fundus findings and clinical history. Molecular genetic testing of mtDNA confirmed the diagnosis of LHON in all four patients. The three patients who experienced recovery had their vision return to 20/50 or better in both eyes. The patient who did not was a heavy consumer of alcohol and tobacco. These findings indicate that Japanese patients with the 14484 mutation have a visual prognosis similar to that of Caucasians with this mutation.

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.