Clinical and laboratory outcomes after umbilical cord blood transplantation in a patient with mucolipidosis II alpha/beta.

Mucolipidosis (ML) II alpha/beta is an autosomal recessive disease caused by reduced enzyme activity of N-acetylglucosamine-1-phosphotransferase. Clinical symptoms of ML II are severe psychomotor delay and dysostosis multiplex; death usually occurs by 5-8 years of age from cardiopulmonary complications. Allogeneic hematopoietic stem cell transplantation (HSCT) has been attempted for ML; however, few reports have documented the detailed outcomes of HSCT for ML. A 26-month-old girl received a human leukocyte antigen 3/6-allele-matched transplant from cord blood. The preparative regimen consisted of fludarabine, cyclophosphamide, 6-Gy total body irradiation, and rabbit antithymocyte globulin. Although comparing before and after cord blood transplantation results, we observed that lysosomal enzyme activities in the plasma decreased by approximately 20-40%. Low serum levels of immunoglobulin A, G2, and G4 were also observed before HSCT; however, these values normalized after transplantation. Despite undergoing HSCT, she was treated twice for bacterial pneumonia with acute respiratory distress syndrome at ages 37 and 38 months. Although HSCT effects on the clinical manifestations were limited, laboratory data including plasma lysosomal enzyme activities and serum levels of immunoglobulin showed improvement.

Early morphological recovery of the optic chiasm is associated with excellent visual outcome in patients with compressive chiasmal syndrome caused by pituitary tumors.

OBJECTIVES: The study objectives are (1) to identify factors predicting the excellent visual recovery after transsphenoidal removal of pituitary tumors and (2) to describe the association of excellent visual recovery and early restoration of symmetry of the decompressed optic chiasm. METHODS: Thirty-five patients with visual symptoms due to pituitary tumors underwent endoscopic endonasal surgery. All patients received perioperative diagnostic magnetic resonance (MR) imaging and ophthalmological assessments within 2 weeks before surgery, within 2 weeks after surgery, and 3 months or later after surgery. Preoperative best-corrected visual acuity (BCVA ≧ 20/20), degree of visual field deficit (VFD, less than half of VF), thickness of retinal nerve fiber layer (RNFL) measured by optical coherence tomography (OCT), and thickness of ganglion cell complex (GCC) measured by OCT were considered for statistical analysis as predictive factors of VF outcome. Multivariate logistic regression models were used in statistical evaluation of data. RESULTS: In the multivariate analysis, RNFL (odds ratio  =  62.137, P < 0.001) and preoperative VFD (odds ratio  =  8.244, P < 0.02) proved to be effective as factors predicting sufficient VF recovery. Postoperative restoration of symmetry of the optic chiasm was related to sufficient VF recovery (P < 0.0001, Fisher's exact test) and RNFL (P < 0.0001, Fisher's exact test). DISCUSSION: Early decompression is crucial for sufficient VF recovery, in particular, while RNFL preserves normal or borderline thickness and while VFD keeps within hemianopia. Morphological reversibility is associated with functional reversibility in the optic chiasm compressed by a pituitary tumor. In particular, early morphological recovery suggests functional recovery, which indicates neurocyte reserve in the compressed optic pathway with functional recovery.

Clinical features of neuromyelitis optica in a large Japanese cohort: comparison between phenotypes.

OBJECTIVE: To analyse clinicoepidemiological features of neuromyelitis optica in a large cohort and to compare the differences between onset age, gender and clinical phenotypes. METHODS: Antiaquaporin-4 antibody (AQP4-ab) levels were tested in 2366 serum samples of patients diagnosed as having central nervous system inflammatory demyelinating disorders by their referring physicians. AQP4-ab was measured by indirect immunofluorescence staining using human AQP4-transfected HEK 293 cells. A blinded analysis was performed and was combined with clinical information. RESULTS: A total of 583 patients (91.4% women) were AQP4-ab-positive. The average onset age was 42.9±15.9 years. According to MRI studies, spinal-cord lesions were detected in 85.3% of the patients, longitudinally extensive transverse myelitis in 72.7% and cerebral lesions in 51.1%. Unilateral or bilateral blindness was observed in 16.2% of patients, 19.8% were associated with Sjögren syndrome, and 13.6% were associated with thyroid diseases. Myelin basic protein was detected in the cerebrospinal fluid of 57.5% patients. In addition, men presented with an older onset age, a greater number of brainstem MRI lesions and positive myelin basic protein in the cerebrospinal fluid. All child-onset patients (<15 years, n=9) presented with optic neuritis as the first symptom, while older-onset patients presented with myelitis. Twenty patients initially developed limited brain lesions, and seven of these patients did not develop optic or spinal lesions during the 1-5-year follow-up period. CONCLUSIONS: The clinical characteristics of AQP4-ab-positive patients were similar. However, optic neuritis was more common in paediatric patients, while myelitis was more common in older patients. A small number of patients exhibited only cerebral, brainstem, or cerebellar lesions during the initial several years and lower Extended Disability Status Scale scores.

Optic nerve head analysis of superior segmental optic hypoplasia using Heidelberg retina tomography.

PURPOSE: To evaluate the optic disc characteristics of eyes with superior segmental optic hypoplasia (SSOH) using the Heidelberg retina tomograph (HRT). PATIENTS AND METHODS: Thirteen eyes of 13 Japanese patients with SSOH were studied with the HRT (software version: 3.0). The group included six males and seven females, with a mean age of 34.7 years. Six optic disc parameters in the six sectors derived from the patients with SSOH were compared with those of 13 eyes of 13 normal controls. In addition, the diagnostic classification performance of the Frederick S Mikelberg (FSM) discriminant function, glaucoma probability score (GPS), and Moorfields regression analysis (MRA) were assessed. RESULTS: When compared with normal subjects, many of the optic disc parameters were significantly altered in SSOH in the superior sectors. The area under the curve (AUC) for the receiver operating characteristic was 0.932 for the rim area, 0.926 for the cup-to-disc area ratio, and 0.882 for the cup shape measure. Among the HRT parameters, the largest AUC (0.988) was found for the cup shape measure in the nasal superior segment. The proportion classified as outside normal limits by the FSM discriminant function was 92.3% (12 eyes). For GPS, six eyes (46.2%) were classified as outside normal limits. For MRA, when borderline cases were considered test-negative or test-positive, 10 eyes (76.9%) or 11 eyes (84.6%) were classified as outside normal limits, respectively. The AUCs were 0.976 for the FSM discriminant function, 0.914 for the MRA overall classification, and 0.710 for the GPS overall classification. CONCLUSIONS: In eyes with SSOH, there is a significant thinning of the rim, especially in the nasal superior sector. Approximately half of the eyes with SSOH were classified as abnormal using indices developed for detecting glaucoma, but the sectorial analysis revealed that the affected sectors were different from those of glaucoma. Optic nerve head measurements using the HRT may be useful in evaluating the optic disc characteristics in eyes with SSOH.

Optic disc measurements using the Heidelberg Retina Tomograph in amblyopia.

PURPOSE: To investigate the characteristics of optic disc parameters in amblyopic eyes in which retinal involvement is uncertain. METHODS: A total of 44 patients with a history of unilateral amblyopia (27 patients with persistent amblyopia and 17 patients with resolved amblyopia) were examined using the Heidelberg Retina Tomograph (HRT) II. Parameters examined included disc area, cup area, cup volume, rim area, rim volume, cup-to-disc area ratio, and mean retinal nerve fiber layer thickness. RESULTS: In patients with persistent amblyopia, the amblyopic eyes were significantly more hyperopic than the fellow eyes. In the HRT parameters, there were no significant differences between the amblyopic and fellow eyes. In addition, after adjusting for refraction, the presence of strabismus, and the disc area, there was no significant difference in any HRT parameter between the amblyopic eyes of patients with persistent amblyopia and the previously amblyopic eyes of patients with resolved amblyopia. CONCLUSIONS: We did not find any strong evidence for the deformity of the optic disc of amblyopic eyes.

Retinal nerve fiber layer thickness in recovered and persistent amblyopia.

PURPOSE: To investigate, using optical coherence tomography (OCT), whether retinal nerve fiber layer thickness (RNFLT) is affected in amblyopic eyes. METHODS: Using OCT (Stratus OCT™ [Carl Zeiss, Dublin, CA]), the RNFLT was measured in 26 patients with persistent unilateral amblyopia and in 25 patients with recovered unilateral amblyopia. The RNFLT was compared between the affected and fellow eyes in patients with persistent amblyopia and in those with recovered amblyopia, and between the amblyopic eyes of patients with persistent amblyopia and the previously amblyopic eyes of patients with recovered amblyopia. RESULTS: In patients with persistent amblyopia and in those with recovered amblyopia, the affected eyes were significantly more hyperopic than the fellow eyes. The average (±standard deviation) RNFLT measured 105.5 ± 14.0 µm for the persistently amblyopic eyes; this value did not significantly differ from that of the fellow eyes (105.2 ± 13.0 µm) or the previously amblyopic eyes of recovered amblyopia (107.1 ± 11.7 µm). Also, logistic regression analysis adjusting for refraction showed no significant difference in the RNFLT between the persistently amblyopic eyes and the previously amblyopic eyes. CONCLUSIONS: Our results indicate that there is no significant change in the RNFLT in amblyopic eyes.

Anti-aquaporin-4 antibody-positive optic neuritis treated with double-filtration plasmapheresis.

PURPOSE: The anti-aquaporin-4 (AQP4) antibody was recently reported to be associated with neuromyelitis optica (NMO). Optic nerve involvements in many NMO cases are bilateral and the prognosis is poor. However, it has been suggested that plasma exchange is effective for those patients when steroid pulse therapy is ineffective. Herein, we report successful treatment of a patient with NMO using double-filtration plasmapheresis (DFPP). CASE: A 22-year-old woman consulted a neurologist for neck pain in March 2008. High-intensity lesions were shown in the cervical spinal cord by T2-weighted magnetic resonance imaging. On July 15, the patient was referred to our department for a headache and pain and blurred vision in the left eye. The best-corrected visual acuity was 20/50 and 20/500 in the right and left eyes, respectively, with visual field defects observed in both. After 3 courses of steroid pulse therapy, anti-AQP4 antibodies were positive. In November, the patient again noticed visual acuity loss in the left eye and was treated by additional steroid pulse therapy, which was not effective. Next, she underwent plasma exchange therapy, though it was stopped due to hypotension and dyspnea. The next day, the patient underwent DFPP treatment and visual function gradually recovered. CONCLUSION: It is important to consider NMO when steroid pulse therapy is not effective. We successfully and safely treated NMO in a young adult patient using DFPP.

Neuroblastoma amplified sequence gene is associated with a novel short stature syndrome characterised by optic nerve atrophy and Pelger-Huët anomaly.

BACKGROUND: Hereditary short stature syndromes are clinically and genetically heterogeneous disorders and the cause have not been fully identified. Yakuts are a population isolated in Asia; they live in the far east of the Russian Federation and have a high prevalence of hereditary short stature syndrome including 3-M syndrome. A novel short stature syndrome in Yakuts is reported here, which is characterised by autosomal recessive inheritance, severe postnatal growth retardation, facial dysmorphism with senile face, small hands and feet, normal intelligence, Pelger-Huët anomaly of leucocytes, and optic atrophy with loss of visual acuity and colour vision. This new syndrome is designated as short stature with optic atrophy and Pelger-Huët anomaly (SOPH) syndrome. AIMS: To identify a causative gene for SOPH syndrome. METHODS: Genomewide homozygosity mapping was conducted in 33 patients in 30 families. RESULTS: The disease locus was mapped to the 1.1 Mb region on chromosome 2p24.3, including the neuroblastoma amplified sequence (NBAS) gene. Subsequently, 33 of 34 patients were identified with SOPH syndrome and had a 5741G/A nucleotide substitution (resulting in the amino acid substitution R1914H) in the NBAS gene in the homozygous state. None of the 203 normal Yakuts individuals had this substitution in the homozygous state. Immunohistochemical analysis revealed that the NBAS protein is well expressed in retinal ganglion cells, epidermal skin cells, and leucocyte cytoplasm in controls as well as a patient with SOPH syndrome. CONCLUSION: These findings suggest that function of NBAS may associate with the pathogenesis of short stature syndrome as well as optic atrophy and Pelger-Huët anomaly.

Anti-aquaporin-4 antibody-positive optic neuritis.

PURPOSE: It has recently been reported that the anti-aquaporin-4 antibody (AQP4-Ab) can be a specific marker of neuromyelitis optica. We present three cases of optic neuritis (ON) where the patients tested positive for AQP4-Ab, but showed no neurological signs. METHODS: Sera were obtained from 32 Japanese patients with ON and no other neurological abnormalities (mean age 46 +/- 20 years). AQP4-Ab was detected by indirect immunofluorescence staining using human-AQP4-transfected HEK 293 cells. RESULTS: AQP4-Ab was positive in three female patients (aged 9, 64 and 82 years). Their illness was characterized by bilateral severe optic nerve involvement, insufficient visual recovery, and autoimmune abnormalities (such as positive antinuclear antibody). Two of these patients experienced recurrent episodes of ON. In at least two episodes, the intracranial portion of the optic nerve showed significant inflammation on magnetic resonance imaging. CONCLUSIONS: These cases indicate that some ON patients have an immunological pathogenesis similar to that seen in neuromyelitis optica. In addition, examination for AQP4-Ab positivity in the initial phase of ON is important in predicting the prognosis, including the possibility of the development of transverse myelitis.

Superior segmental optic nerve hypoplasia in youth.

PURPOSE: The clinical characteristics of superior segmental optic nerve hypoplasia (SSOH) in youth were investigated to help establish diagnostic criteria. METHODS: Eleven eyes of seven young patients (male/female ratio, 3/4; age, 15.1 +/- 3.4 years) who had good visual acuity and inferior visual field defects (VFDs) were evaluated. Goldmann and Humphrey perimetries and optic disc morphology were analyzed, and the patients were prospectively followed for a long period. RESULTS: Visual field defects were wedge shaped and oriented to the blind spot, but discontinuous in mild cases. Nerve fiber layer defects (NFLDs) were consistent with the VFDs. The optic disc appearance was variable, with double ring signs in seven eyes, small discs in three eyes, and an incomplete topless disc in one eye. The mothers of none of the patients had gestational diabetes. Visual field defects did not progress during the prospective 8.3 +/- 1.3 years follow-up. CONCLUSIONS: Characteristic VFD patterns on Goldmann perimetry and corresponding NFLDs are important in the diagnosis of SSOH, but not optic disc morphology.

Pupillography of relative afferent pupillary defects in amblyopia associated with peripapillary myelinated nerve fibers and myopia.

Pupillary responses to light were recorded in three patients with unilateral extensive myelinated nerve fibers and amblyopia by means of binocular infrared video pupillography. All of the patients had an afferent pupillary defect in the eye with myelinated nerve fibers. This finding supports the notion that this type of amblyopia is a severe form of anisometropic amblyopia that is often resistant to treatment.

Pupillography of automated swinging flashlight test in amblyopia.

Relative afferent pupillary defects (RAPDs) in amblyopia have been reported, and it is widely accepted that amblyopes can have an RAPD. We investigated whether or not this could be confirmed by the use of binocular pupillography. We examined twelve patients (6 males and 6 females, aged 7-57 years) with unilateral amblyopia associated with anisometropia and/or strabismus, using binocular infrared video pupillography (Newopto, Kawasaki, Japan). Eight normal subjects were also tested in the same manner. Two patients' data had to be excluded because of poor recording quality. Only one patient with moderate anisometropic amblyopia was found to have reduced contraction amplitude in the amblyopic eye, and one patient with a borderline pupillary defect. The other amblyopes, some of whom showed even denser amblyopia, did not have a pupillary defect. This study has confirmed that only a small proportion of amblyopes have a reduced pupillary contraction amplitude in the affected eye, as established by pupillographic recordings, and even these amblyopes are not necessarily associated with dense amblyopia.

Assessment of axonal degeneration along the human visual pathway using diffusion trace analysis.

PURPOSE: The effectiveness of diffusion trace value analysis for non-invasive assessment of retinal ganglion cell (RGC) axonal degeneration at multiple anatomic levels along the human visual pathway under clinical setting was evaluated. DESIGN: Imaging study. METHODS: Ten patients with unilateral chronic optic neuropathy of varying cause and 16 age-matched normal subjects were studied. Trace, a tensor invariant that is considered to be a sensitive index for pathologic changes in axons, was analyzed at nine anatomic sites in each subject, namely, bilaterally at the level of the optic nerves, uncrossed chiasmal fibers, optic tracts and optic radiations, and crossed chiasmal fibers, using a 3.0 Tesla magnetic resonance imaging system. RESULTS: Trace values of the optic nerve and uncrossed chiasmal fibers ipsilateral to the affected eye, the crossed chiasmal fibers, and optic tracts bilaterally were significantly higher than those of the corresponding anatomic sites in normal subjects. The optic nerve and uncrossed chiasmal fibers ipsilateral to the unaffected side and optic radiations, bilaterally, had trace values which were not significantly different from the values of the corresponding anatomic levels in normal subjects. The increase in trace value in the optic nerve and uncrossed chiasmal fibers ipsilateral to the affected side was greater than those of the crossed chiasmal fibers and optic tracts. CONCLUSIONS: Findings are highly consistent with a degenerative process of RGC axons and trace values are quantitatively well correlated to predicted pathology at the given anatomical sites. Trace value measurement at multiple sites along fiber pathways appears to be a powerful addition to clinical assessment of the functionality of components of the visual pathways during various stages of a pathologic process.

Negative scotopic ERG and photopic ERG ON response impairment in a patient with normal dark adaptation.

PURPOSE: To present ocular findings in a patient who showed negative scotopic electroretinogram (ERG) and reduced ON response, but normal dark adaptation. CASE: An 18-year-old Japanese male patient who complained of severe asthenopia. His corrected visual acuities were 1.2 in both eyes. His fundi were normal. He had normal contrast sensitivity and normal dark adaptation. METHODS: The patients underwent ERG (including the standard protocol and photopic long flash recordings). RESULTS: The amplitudes of the rod ERG b-wave were reduced. The scotopic standard combined ERG response showed negative configuration. The photopic response to long flash revealed the reduced b-wave (ON response), while the amplitude of the first peak of the d-wave (OFF response) was within the normal range. CONCLUSIONS: Postsynaptic abnormalities in both the rod and cone ON-pathways, which are often found in patients with night blindness, were suggested in the ERG findings, but the dark adaptation of our patient was normal. Neuromuscular evaluation of the patient and ophthalmological evaluation, including ERG, of his parents were normal. To our knowledge, the ophthalmological and electrophysiological findings of our patient cannot be attributed to any known clinical entity.

Pupillography of relative afferent pupillary defect contralateral to monocular mature cataract.

CASE REPORT: Few previous reports have documented a relative afferent pupillary defect (RAPD) in the eye contralateral to a dense unilateral cataract. We report pupillographic findings of a 55-year-old man with a mature cataract in the left eye and an RAPD in the right eye, whose RAPD disappeared after cataract surgery in his left eye. Using binocular infrared video pupillography, we recorded the pupillary responses of the two eyes simultaneously during an automated swinging flashlight test before and after the cataract surgery. The average contraction amplitude in both eyes was significantly larger when the unaffected left eye was stimulated before the cataract surgery, but this difference in contraction amplitude disappeared after surgery on the left eye. COMMENTS: An RAPD was shown quantitatively with a pupillographic technique in the eye contralateral to a mature cataract, confirming previous studies that indicate a dense cataract may produce a small but definite RAPD in the contralateral eye. Such an RAPD associated with a dense cataract must be taken into consideration when evaluating patients with unilateral visual loss.

Visual cortical contribution to open-loop and feed-back control of convergence eye movements in the cat.

Open-loop and closed loop controls in convergence eye movement have been reported by human psycho-physical studies. To investigate the visual cortical involvement in open-loop convergence eye movement, we trained a cat to elicit anticipatory convergence (convergence eye movement before the onset of target movement) by using an approaching visual target with a preceding alarm signal. After 1-2 weeks of training, anticipatory convergence was observed in more than half of the trials in seven cats. The frequency of occurrence of anticipatory convergence was significantly decreased after electrocoagulation in the convergence-related region of the lateral suprasylvian (LS) area, an extrastriate visual cortex of the cat. On the other hand, the localized injection of Muscimol, a GABA-A agonist, reduced visually evoked convergence, but caused no significant effects to anticipatory convergence. These differential results suggest that the LS plays a role in both open-loop and feed-back control of convergence eye movement, and a GABA-A sensitive subregion is involved in the feed-back control of convergence eye movement.

Effect of the background on the disparity-induced ramp vergence response in humans.

PURPOSE: Our purpose was to investigate the changes in the dynamic property of vergence eye movements caused by changes in the co-existing stationary background in the central visual field. METHODS: Disparity-driven target movement was presented virtually by a head-mounted liquid-crystal display. Two targets were used: a bar-shaped target that moved between 2 and 0.5 m along the mid-sagittal line at a speed of 50 cm/s (vergence target) and a background image of a cross-shaped target that stayed at a distance of 2 m (background target). Eight normal subjects participated in the experiments. The subject was asked to follow the vergence target while the configuration of the background target was randomly changed among four conditions in each experiment: the length (experiment 1) or the width (experiment 2) of the horizontal and vertical lines composing the cross of the background target was each randomly changed among four conditions. A limbus tracker was used to measure eye movements. RESULTS: In experiment 1, there was a negative correlation between the amplitude of the vergence eye movements and the lengths of the lines of the cross in each of five subjects (mean r = 0.018, n = 48 in each subject). Similarly, in experiment 2, there was a negative correlation between the amplitude of the vergence eye movements and the width of the lines of the cross in each of 8 subjects (mean r = -0.12, n = 48 in each subject). CONCLUSION: The vergence response to a target object significantly differs depending on the texture of background objects on the visual axis.

PIII and derived PII analysis in a patient with retinal dysfunction with supernormal scotopic ERG.

PURPOSE: To present electroretinographic (ERG) findings in a patient with retinal dysfunction with supernormal scotopic ERG, and to analyze rod and cone PIII components and rod inner nuclear layer (derived PII) responses. PATIENT: A Japanese 11-year-old girl complained of poor visual acuity. There was no parental consanguinity in her family. The corrected visual acuity was 0.7 in both eyes. No abnormal finding was observed in both fundi. METHODS: The patient underwent full-field ERGs. Rod and cone a-waves were analyzed using photoreceptor models. The derived PII responses were analyzed using a technique described by Hood and Birch. RESULTS: In the photopic ERG, responses to single flash and 30-Hz flicker were attenuated. In the scotopic ERG, b-wave was supernormal in amplitude in response to intense flashes, but smaller than normal and markedly delayed over a lower range of flash intensities. By the PIII analysis, phototransductions (values of S) of both rod and cone were remarkably decreased. The derived PII responses for this patient were larger than the responses for normal subjects, and the onset of the PII responses in this patient are significantly delayed compared to those in normal subjects. CONCLUSIONS: The ophthalmological findings in this patient are consistent with previous publications of this disease. Although it has been reported that the sites of disease action were beyond the outer segment (values of S were within the normal range), our results suggest that photoreceptors could be involved in sites of disease action in at least some patients with this disease.