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.

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.

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.

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.

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.

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.

Near-infrared spectroscopy of the visual cortex in unilateral optic neuritis.

PURPOSE: To examine the occipital-lobe activation of patients with optic neuritis using near-infrared spectroscopy. DESIGN: Experimental study. METHODS: NIRS was performed on five patients with acute unilateral optic neuritis during monocular visual stimulation. As controls, six normal subjects were also tested in the same manner. RESULTS: In the patients with optic neuritis, the changes in the hemoglobin concentrations (oxyhemoglobin, deoxyhemoglobin, and total hemoglobin) in the occipital lobe were found to be markedly reduced when the clinically affected eyes were stimulated compared with the fellow eyes. The response induced by the stimulation of the affected eye was decreased, even when the patient's visual acuity improved to 20/20 in the recovery phase. There was no difference in the concentration changes between the two eyes in the control subjects. CONCLUSIONS: NIRS may be useful in detecting visual dysfunction objectively and noninvasively in patients with visual disturbance, especially when used at the bedside.

Rod and cone a-waves in central retinal vein occlusion.

PURPOSE: To evaluate rod and cone a-waves in cases with unilateral central retinal vein occlusion (CRVO). METHODS: Scotopic and photopic flash electroretinograms (ERGs) were recorded in seven patients aged 54-84 with unilateral hemorrhagic CRVO. Rod and cone a-waves were analyzed using photoreceptor models, and Rm(p3) (maximum a-wave amplitude) and S (sensitivity) were calculated. RESULTS: Decreased rod log S was found in all seven cases, and decreased cone log S was found in five cases. In only one case, rod log S in the fellow eye was decreased. The alterations in rod and cone log Rm(p3) were smaller than those in rod and cone log S. Of three cases in which ERGs could be recorded again after a certain follow-up period, rod log S and cone logS became larger in two cases and smaller in one case. CONCLUSIONS: The change in the phototransduction cascade was confirmed not only in rods but also in cones in five of our seven cases of CRVO. The ERG findings might reflect the functional change in the photoreceptor layer after the onset of CRVO.

[Progression of cluster headache to Raeder's syndrome with marked response to corticosteroid therapy: a case report].

A 42-year-old man complained of severe left orbital pain for 7 months. The diagnosis of cluster headache was made on the basis of diagnostic criteria formed by the International Headache Society. Sumatriptan was effective in relieving pain to a certain degree, but the frequency of the occurrence of pain gradually increased. Subsequently, he presented sensory disturbances in the left trigeminal nerve, and was admitted to our hospital. On admission, his neurological examination revealed left miosis and paresthesia in the first branch of the left trigeminal nerve. Neither anhidrosis nor ptosis was noted. His autonomic failure was consistent with post-synaptic disturbance as determined by pharmacological analysis for pupil's function. On the basis of the unique combination of neurological sings and symptoms including the unilateral headache, partial Horner's syndrome, and V1 sensory disturbance, we diagnosed him as having Raeder's syndrome. To exclude the possibility of a lesion in the Gasser ganglion of the middle fossa of the cranium or carotid artery causing symptomatic Raeder's syndrome, imaging studies including brain MRI, cervical MRA, and Doppler ultrasonography were performed, which revealed normal findings. We started him on oral prednisolone at 1 mg/kg once a day, which resulted in a rapid and dramatic suppression of pain. Thus, this case showed a progression from cluster headache to idiopathic Raeder's syndrome, which suggests that these two disorders might share common pathological and anatomical lesions.

[Evaluation of macula in patients with branch retinal vein occlusion using multifocal electroretinogram and optical coherence tomography].

PURPOSE: To evaluate the functions of the macular area in patients with branch retinal vein occlusion (BRVO) by using multifocal electroretinograms (mERG) and optical coherence tomography(OCT). METHODS: mERGs were recorded from 18 eyes of 18 patients with BRVO. An array of 103 hexagonal elements was displayed on a monitor. The latency (ms) and response density (nV/deg2) of mERGs were measured for 7 central locations. The peak and troughs were labeled N1, P1 and N2, respectively. OCT was used to measure the foveal retinal thickness. RESULTS: Statistically significant correlation was found between visual acuity(log MAR) and P1-N1 response density (r = - 0.629, p < 0.05) and N2 latency(r = 0.619, p < 0.05). Foveal retinal thickness had the significant statistic correlations with P1-N1 response density (r = -0.750, p < 0.0001), P1-N2 response density (r = -0.520, p < 0.05) and N2 latency (r = 0.488, p < 0.05). CONCLUSIONS: In 18 BRVO patients, mERGs from the central retinal area were significantly correlated with foveal retinal thickness measured by OCT and with visual acuity. The mERG recording is sensitive to morphological changes and functional disorders induced by BRVO.

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.

Central and peripheral visual interactions in disparity-induced vergence eye movements: I. Spatial interaction.

PURPOSE: To evaluate the interaction between central and peripheral disparities in the initiation of vergence eye movements. METHODS: Eye movements were recorded in eight normal subjects using an infrared limbus tracker. Three-dimensional visual stimuli were back projected onto a tangent screen by using two liquid crystal display (LCD) projectors through crossed polarizers. The central target was a vertical bar, which always jumped from 2 to 1 m. The peripheral target was a random-dot pattern that jumped from 2 to 0.75, 1, or 1.5 m (near planes), 2 m (no change), or 3 m (far plane) simultaneously with the central target jump. Latency, amplitude at 150 ms, and average amplitude over 1 to 2 seconds after vergence onset; peak velocity; and the main-sequence relationship of the initial vergence response were calculated. How far the central target appeared to jump was scored subjectively. RESULTS: In half of the subjects, there was a clear effect of the peripheral disparity on the dynamics of the vergence response to the central disparity. The amplitude of vergence at 150 ms, as an index of open-loop gain, was significantly greater when the peripheral target moved closer, but steady state amplitude (average during 1-2 seconds) did not change, and the vergence latency was significantly greater when the peripheral target jumped away. There was no obvious relationship between the perceived amount of movement of the central target and the parameters of the dynamic properties of the vergence response. CONCLUSIONS: Peripheral disparity can modulate the dynamics of the initial vergence response to a central disparity and is probably independent of the perception of motion in depth.

Effects of lesions of the cerebellar oculomotor vermis on eye movements in primate: binocular control.

The effects of lesions of the dorsal 'oculomotor' cerebellar vermis on binocular oculomotor functions in three monkeys were examined. Prominent findings included (1) a convergence bias during monocular fixation, i.e., an 'esodeviation' in the absence of disparity cues, (2) a loss of comitancy, i.e., alignment varies more with orbital position, (3) abnormal saccade yoking producing saccade disconjugacy, and (4) defects in prism-induced phoria adaptation. There was also a suggestion of a disturbance in the dynamic properties of disparity-induced vergence. These findings point to a role for the 'oculomotor' vermis in binocular aspects of the control of eye movements.

ERG rod a-wave in Oguchi disease.

We analyzed the change in the ERG rod a-wave waveform during the course of dark adaptation in two patients with Oguchi disease. Two Japanese patients showed a homozygous arrestin 1147delA mutation. Scotopic flash ERGs were recorded after different periods of dark adaptation. ERG rod a-waves were obtained after subtraction of the cone ERG contribution. The rod a-waves were fitted with a model of the rod receptor signal. The parameters, Rm(p3) (maximum a-wave amplitude) and S (sensitivity) were calculated. Longer periods in the dark produced larger rod a-wave but only to the first flash presented. The amplitude of the response to subsequent flashes was essentially independent of the period of dark adaptation. Rm(p3) increased with advance of dark adaptation. However, S was nearly constant. Our results suggest that the cause of delayed dark adaptation is not to be sought in the activation of phototransduction process or the regeneration of rhodopsin per se but rather in the deactivation process of the phototransduction cascade.

Pupillary and cardiovascular responses to a video movie in senior human subjects.

The effects of watching video movies on autonomic functions were estimated by measuring changes in pupillary and cardiovascular parameters in 10 senior subjects. The subjects looked at a series of video images (with accompanied sounds) taken during the execution of motor vehicles. The images were rear-projected on a large screen for 15 min. Pupil diameter and parameters of the light reflex were measured by an infrared pupillometer before and after the video presentation. Their electrocardiograms (ECG) and blood pressure were measured continuously. Subjects were divided into two groups depending on their values of blood pressure and fasting plasma glucose level. Subjects in Group A had blood pressures of less than 140 mm Hg and a fasting plasma glucose level of less than 7 mmol/dl (normal group). Other subjects were included in Group B (mild hypertension or diabetes mellitus group). While changes in pupillary light reflex after video viewing were minimal in the members of Group A, amplitudes of the pupillary reflex in the members of Group B varied over a significantly wide range. By the spectral analysis of cardiovascular rhythm, %LF and %HF components of blood pressure rhythm were significantly different between the two groups before video viewing. However, the ratios of frequency components before and after video viewing were not significantly different between the two groups. Our findings suggest that pupillary light reflex was less precisely controlled in subjects with mild autonomic dysfunction after prolonged audiovisual stimulation.

Multifocal electroretinogram in patients with central serous chorioretinopathy.

PURPOSE: To assess local retinal function of macula in patients with central serous chorioretinopathy (CSC). METHODS: Multifocal electroretinograms (ERGs) were recorded in 5 patients with unilateral CSC and 20 normal subjects. The waveforms from the central retina within 5 degrees of visual angle were analyzed. The first negative trough was designated as N1, the first positive peak as P1, and the second trough as N2. RESULTS: The multifocal ERG amplitudes were significantly reduced at the first attack of CSC in all patients compared with the values in the normal controls, for P1-N1 (P <.01) and for P1-N2 (P <.01). Multifocal ERG latencies of the patients significantly increased compared with normal controls, for P1 (P <.01) and N2 (P <.01). After the resolution of retinal detachment, although the multifocal ERG amplitudes increased markedly, they did not improve to the normal level during the follow-up period (4-23 months). CONCLUSIONS: Persistent functional impairment of the retina was found by multifocal ERGs in patients with CSC after the resolution of subretinal fluid. A topographical analysis of the multifocal ERG is useful in the clinical observation of CSC.

Electroretinographic findings in three family members with X-linked juvenile retinoschisis associated with a novel Pro192Thr mutation of the XLRS1 gene.

PURPOSE: To present ocular findings in three family members with X-linked juvenile retinoschisis (XLRS) associated with a novel Pro192Thr mutation. CASES: We examined 21- (Case 1), 17- (Case 2), and 10-year-old (Case 3) male patients who showed wheel-like cystic lesions in the macula and a silver-gray reflex in the peripheral retina. Case 2 was a cousin of Case 1. Case 3 was a brother of Case 2. METHODS: Scotopic electroretinogram (ERG) (dim and bright flash), oscillatory potentials, photopic ERG, and 30-Hz flicker responses were recorded in each patient. The XLRS1 gene was analyzed in patient blood samples by a direct sequencing method. RESULTS: A novel missense mutation (Pro192Thr) was identified in the XLRS1 gene in each patient. Variable b/a ratios upon scotopic bright flash stimulation were evident (Case 1: right 1.16, left 1.20; Case 2: right 0.98, left 1.01; Case 3: right 0.81, left 0.83). Only Case 3 showed the typical "negative" waveform. The amplitude of rod b-waves was significantly decreased in all patients. CONCLUSIONS: Three cases with a novel Pro192Thr mutation showed the phenotypic variation in ERG, especially in b/a ratio, which has been considered an important diagnostic parameter.

[Multifocal electroretinograms in patients with retinal vein occlusion].

PURPOSE: To investigate waveform changes of multifocal electroretinograms(mERG) in patients with retinal vein occlusion(RVO). METHODS: Nine eyes of 8 patients with RVO and 29 eyes of 29 normal subjects were examined using mERG. An array of 103 hexagonal elements was displayed on a monitor. mERG latencies(ms) and response densities (nV/deg2) were measured for center area(Ct) and for each of four quadrant areas. The peak and troughs were named N1, P1 and N2, consecutively. RESULTS: In pathological quadrants, although the response densities were abnormal in only one eye, latencies of the N2 and P1 were prolonged in 7 eyes and in 2 eyes, respectively(over 1 SD-2 SD). The latencies were significantly prolonged compared with those of normal eyes(p < or = 0.03, U-test). On the other hand, in the central area, although the latencies were abnormal in 3 eyes, the response densities were reduced in 6 eyes(over 1 SD-2 SD). The response densities were significantly reduced compared with those of normal eyes(p < or = 0.024, U-test). CONCLUSIONS: Both peak latencies in pathological quadrants and response densities in the central retinal area can be sensitive indicators of retinal dysfunction caused by RVO. The mERG system is useful for detecting local retinal dysfunction in patients with RVO.