Masato Wakakura

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 ≥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 ≥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.

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

PURPOSEnTo investigate the incidence and clinical significance of primary or proposed secondary mitochondrial DNA (mtDNA) mutations in Japanese patients with Lebers hereditary optic neuropathy (LHON).nnnMETHODSnBlood 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.nnnRESULTSnPrimary 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.nnnCONCLUSIONSnJapanese 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.

Baseline Features of Idiopathic Optic Neuritis as Determined by a Multicenter Treatment Trial in Japan

BACKGROUNDnAn 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.nnnCASESnInitially, 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.nnnOBSERVATIONSnThe 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.nnnCONCLUSIONSnThe baseline clinical features of optic neuritis in the Japanese patients have been defined. Some racial differences in the characteristics of the disease may exist.

Multicenter Clinical Trial for Evaluating Methylprednisolone Pulse Treatment of Idiopathic Optic Neuritis in Japan

BACKGROUNDnA 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.nnnCASESnSixty-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.nnnOBSERVATIONSnThe 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).nnnCONCLUSIONSnPulse 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.

Glucose hypermetabolism in the thalamusof patients with essential blepharospasm

AbstractEssential blepharospasmn(EB) is classified as a formnof focal dystonia characterized byninvoluntary spasms of the musculaturenof the upper face. The basicnneurological process causing EB isnnot known. The purpose of thisnstudy was to investigate cerebralnglucose metabolism in patientsnwith EB whose symptoms werensuppressed by an injection ofnbotulinum-A toxin. Earlier studiesnwere confounded by sensorynfeedback activities derived fromndystonic symptom itself. Cerebralnglucose metabolism was examinednby positron emission tomographyn(PET) with 18F-fluorodeoxyglucosen(FDG) in 25 patientsn(8 men and 17 women; agen52.6 ± 10.1 years) with EB. Thenpatients were awake but with thenspasms suppressed by an injectionnof botulinum-A toxin. Thirty-eightnnormal volunteers (14 men and 24nwomen; age 58.2 ± 7.3 years) werenexamined as controls. The differencenbetween the two groups wasnexamined by statistical parametricnmapping (SPM99). A significantnincrease in the glucose metabolismnwas detected in the thalamus andnpons in the EB patients. Hyperactivitynin the thalamus may be a keynpathophysiological change commonnto EB and other types of focalndystonia. The activity of the striatumnand cerebellum are likely tonbe sensory dependent.

Photophobia in essential blepharospasm—A positron emission tomographic study†‡

To localize regional alterations in cerebral glucose metabolism in essential blepharospasm (EB) patients with photophobia. We have studied 22 EB patients by performing positron emission tomography and [18F]‐fluorodeoxyglucose analysis. The patients were classified into two subgroups, namely, EB with photophobia (P group) and EB without photophobia (NP group), and compared with a healthy control group (n = 44). There were no significant differences between the two patient groups with respect to the severity of motor symptoms or the duration for which the condition persisted. The FDG‐PET images were analyzed using the statistical parametric mapping software. As compared to the control group, the P group exhibited significant hypermetabolism in the thalamus (P = 0.002), while the NP group exhibited significant hypometabolism in the dorsal midbrain, especially, in the superior colliculus (P = 0.005). The P group exhibited significant hypermetabolism in the thalamus and the dorsal midbrain as compared to the NP group (P < 0.001). These findings suggest that photophobia in EB patients may be associated with abnormal hyperactivity in the thalamus. Either hyperactivity of the thalamus or hypoactivity of the superior colliculus, or both may be associated with excessive blinking in these patients.

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.

Gray matter density increase in the primary sensorimotor cortex in long-term essential blepharospasm.

In this study, we investigated gray matter density in essential blepharospasm (EB) patients, focusing on the duration of disease and severity of symptoms. We studied 32 patients (10 males and 22 females; age, 55.0 ± 6.5years) with EB and 48 controls (15 males and 33 females; age, 54.4 ± 10.3years) by using 3D T1-weighted magnetic resonance imaging and voxel-based morphometry. We defined an activity index (AI) that reflects the severity and duration of EB symptoms in each patient. The difference between the 2 groups was examined by statistical parametric mapping software (SPM8). After controlling for age, gray matter density increased in the bilateral primary sensorimotor cortex (S1M1) and cingulate gyrus. The gray matter density in the bilateral S1M1 was found to have a significant positive correlation with the duration of disease and a more robust correlation with AI. The correlation coefficients, after correcting for age, in the S1M1 and left cingulate gyrus were as follows: with duration, right S1M1, 0.72 (P<0.00001); left S1M1, 0.72 (P<0.00001); and left cingulate gyrus, 0.33 (not significant); and with AI, right S1M1, 0.81 (P<10(-7)); left S1M1, 0.74 (P<0.00001); and left cingulate gyrus, 0.43 (P<0.05). The increase in gray matter density in the S1M1 and cingulate gyrus might be a secondary effect caused by long-term hyperactivity in these areas instead of a predisposing factor.

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

Summary: The 14484 mutation in the ND6 gene of mitochondrial DNA (mtDNA) is a genetic mutation associated with Lebers 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 alchol and tobacco. These findings indicate that Japanese patients with the 14484 mutation have a visual prognosis similar to that of Caucasians with this mutation.

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

Abstractu2002· Purpose: This study was conducted to detect the presence of muscarinic or nicotinic receptors in cultured retinal neurons and Müller cells.u2002· 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 µM, which was significantly blocked by α-bungarotoxin at 50 nM. No response to nicotine could be detected in Müller cells. Approximately 50% of neurons responded to muscarine at 50 µM, but 500 µM 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 µM induced the most significant and rapid increase in [Ca2+]i both in neurons and Müller cells. McN-A-343 administration at 0.05 µM 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 µM. · 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.