Pseudoxanthoma elasticum overlaps hereditary spastic paraplegia type 56.

PURPOSE: Pseudoxanthoma elasticum (PXE) is a recessive disorder involving skin, eyes and arteries, mainly caused by ABCC6 pathogenic variants. However, almost one fifth of patients remain genetically unsolved despite extensive genetic screening of ABCC6, as illustrated in a large French PXE series of 220 cases. We searched for new PXE gene(s) to solve the ABCC6-negative patients. METHODS: First, family-based exome sequencing was performed, in one ABCC6-negative PXE patient with additional neurological features, and her relatives. CYP2U1, involved in hereditary spastic paraplegia type 56 (SPG56), was selected based on this complex phenotype, and the presence of two candidate variants. Second, CYP2U1 sequencing was performed in a retrospective series of 46 additional ABCC6-negative PXE probands. Third, six additional SPG56 patients were evaluated for PXE skin and eye phenotype. Additionally, plasma pyrophosphate dosage and functional analyses were performed in some of these patients. RESULTS: 6.4% of ABCC6-negative PXE patients (n = 3) harboured biallelic pathogenic variants in CYP2U1. PXE skin lesions with histological confirmation, eye lesions including maculopathy or angioid streaks, and various neurological symptoms were present. CYP2U1 missense variants were confirmed to impair protein function. Plasma pyrophosphate levels were normal. Two SPG56 patients (33%) presented some phenotypic overlap with PXE. CONCLUSION: CYP2U1 pathogenic variants are found in unsolved PXE patients with neurological findings, including spastic paraplegia, expanding the SPG56 phenotype and highlighting its overlap with PXE. The pathophysiology of ABCC6 and CYP2U1 should be explored to explain their respective role and potential interaction in ectopic mineralization.

[Pediatric myasthenia with ocular involvement]. / Myasthénie chez l'enfant avec atteinte oculaire.

PURPOSE: Myasthenia is a rare disease in children, with an estimated incidence of 1 to 5 per million children. However, the potential severity of its consequences and the existence of specific treatments require prompt diagnosis by pediatric ophthalmologists. METHODS: Retrospective review of patient records. Patients were identified from a rare disease database. Patients under the age of 18 years with confirmed diagnosis of myasthenia and ocular symptoms seen in a specialized clinic between 2005 and 2021 were included. RESULTS: Twenty-six (16 girls) with confirmed myasthenia and ocular symptoms were included. Ten patients had definite autoimmune myasthenia gravis (AIMG); 6 had suspected AIMG with negative antibody testing. Six patients had definite congenital myasthenic syndrome (CMS); 4 had suspected CMS with no evidence of mutation. Mean age at diagnosis of myasthenia was 5 years-3 years and 5 months for CMS and 6 years and 3 months for AIMG. Male to female (M:F) ratio was 6/10 for autoimmune myasthenia gravis and 4/6 for CMS. Ptosis was present in all cases; strabismus in 21 patients (68%). The clinical forms of myasthenia were ocular myasthenia in 12 patients (10 AIMG and 2 CMS), generalized in 12 patients (7 CMS and 5 AIMG) and secondary generalization of ocular myasthenia in 2 patients (2 AIMG). DISCUSSION: These results are based on only 26 cases, which can be explained by the rarity of this diagnosis in children. As in adults, the first signs are often ophthalmologic - ptosis alone or associated with strabismus. Diagnosis is difficult because of the absence of clinical signs, laboratory tests or electrophysiological signs with high sensitivity. Thus, the work-up may remain completely negative in secondarily proven forms. In addition, electroneuromyograms and oculomotor recordings in small children are more difficult to perform than in adults. For these reasons, the clinical examination is essential. In the case of strong suspicion, all additional medical examinations are carried out in a day unit, in order to reach a positive diagnosis of myasthenia. The so-called "congenital" forms, which are genetic, are proportionately higher than in adults, and diagnosis and treatment are often more difficult than in the classic autoimmune forms. CONCLUSION: Myasthenia can affect children from a very young age and can present as ptosis, initially isolated or associated with strabismus. Diagnosis and treatment may be difficult and should be organized in specialized centers.

[Leber hereditary optic neuropathy: differential diagnosis]. / Neuropathie optique héréditaire de Leber : le diagnostic différentiel.

The diagnosis of Leber hereditary optic neuropathy is suspected in the siblings of an affected person that complains of a decrease in visual acuity. It can also be suspected in a young subject, especially a male, with no medical history that presents with an optic neuropathy. Leber hereditary optic neuropathy is a diagnosis of exclusion. The search for differential diagnoses is essential in all cases, even when a mutation of the mitochondrial DNA was found in the patient of in a healthy carrier maternal relative. This is the interest of multimodal imaging and electrophysiology that allow to exclude retinal pathology mimicking optic neuropathy. A neuroradiological assessment must be systematically prescribed to eliminate a compressive lesion and/or intracranial hypertension. This assessment also provides information on a possible hypersignal of the optic nerve, the appearance of which can be an argument for orientation towards different causes of optic neuritis. Finally, a deficiency or toxic cause must be ruled out.

[Screening and prevention of toxic optic neuropathies due to anti-mycobacterium therapies: proposal of recommendations]. / Dépistage et prévention des neuropathies optiques toxiques aux anti-mycobactériens : proposition de recommandations.

While treatment of pulmonary infections by Mycobacterium tuberculosis is currently only rarely the cause of iatrogenic complications, treatment of atypical mycobacterial infections often requires prolonged treatment duration, which can lead to toxic optic neuropathies. This review summarizes the indications for such prolonged treatment and risk factors for toxic optic neuropathies when using ethambutol, isoniazid and/or linezolid and proposes customized screening recommendations.

Toxic optic neuropathy due to voriconazole: possible potentiation by reduction of CYP2C19 activity.

OBJECTIVE: Voriconazole is an antifungal treatment with central neurotoxicity. Modifications of the electroretinogram can explain some of its visual complications: visual hallucination, blurred vision, altered visual perception or photophobia. However, reports from the literature or the French pharmacovigilance centers evoked toxic optic neuropathy due to voriconazole. The aim of this report is to analyze the role of voriconazole in the occurrence of toxic optic neuropathy or the role of the combination of voriconazole with other neurotoxic drugs. PATIENTS AND METHODS: We report the case of a 15-year-old young boy treated with voriconazole and ethambutol for a severe lung infection due to aspergillosis and mycobacterium tuberculosis in the mucoviscidosis and pulmonary transplantation who developed a toxic optic neuropathy. A review of the literature on the role of ethambutol on the activity of CYP2C19 and its relationship with the serum concentration of voriconazole was conducted. RESULTS: In our patients, visual acuity recovered after discontinuation of voriconazole. Other cases of toxic optic neuropathy due to voriconazole were reported in pharmaco-vigilance databases, often in association with ethambutol. CONCLUSIONS: Ethambutol can reduce the activity of CYP2C19 leading to an increase of voriconazole concentration. Thus, it potentiates its risk of adverse event. Such mechanism leading to this neuro ophthalmological adverse effect would have an important clinical involvement. It would require a stricter monitoring and screening of patients treated by combination of neurotoxic molecules and VRZ to detect an adverse event.

Effects of visual disorders on the academic achievement of French secondary school students.

PURPOSE: This study aimed to determine the relationship between the presence of visual problems and academic success, in a population of students aged 15-22 years. METHODS: This was a prospective, nonrandomized study involving clinical testing and structured interviews. At recruitment (September 2012 to April 2013), participants were asked to answer a questionnaire consisting of 28 questions aiming to identify symptoms commonly related to visual disorders. Each question was graded from 0 (no symptoms) to 2 (frequent). This questionnaire was followed by a visual screening including binocular function. If a problem was identified, participants were referred to an ophthalmologist for a comprehensive examination and an orthoptic work-up (September 2012 to June 2013). Participants returned in September 2013 for a follow-up. The findings were analyzed regarding academic grades and the scores obtained during national examinations in June 2014. RESULTS: Many participants in this study had visual disorders and the presence of these disorders was not associated with the expression of visual discomfort: 24.3% of participants expressed visual discomfort while 86.5% had visual disorders. More than half of the participants had hyperopia often associated with binocular vision problems, which they were not aware of because both their distance and near visual acuity were good. CONCLUSION: Although the results of this study cannot be extrapolated to all young people aged 15-22 years, the study confirms the link between visual problems and academic achievement while emphasizing the high prevalence of such problems in the population studied.

[Raxone in the Leber optical neuropathy: Parisian experience]. / Raxone dans la neuropathie optique de Leber : retour d'expérience parisienne.

INTRODUCTION: Leber's Hereditary Optic Neuropathy (LHON) causes a rapid and severe decrease in visual acuity. Raxone® (Idebenone, Santhera) is the only drug to have a European Marketing Authorization for the treatment of this optic neuropathy. It can be proposed in the first months after the onset of this optic neuropathy, according to an international consensus meeting. PATIENTS AND METHODS: Retrospective study of the efficacy of Raxone® on the visual acuity of patients with genetically confirmed LHON who were followed in four Parisian hospitals. The primary endpoint is the best recovery of LogMar visual acuity between baseline and the end of follow-up. The secondary endpoints are the evolution of LogMar visual acuity of the best eye at baseline and change in LogMar visual acuity for each eye considered separately. RESULTS: Seventeen patients, three women and 14 men, mean age 34.2 years, naive to treatment with Raxone® were included in this study. The mean duration of treatment was 11.0±6.6 months. A mitochondrial DNA mutation was found in all patients. Only 2 had the 14484 mutation. A recovery of better LogMar visual acuity was found at the end of the treatment for 4 eyes (23.5 %), and a deterioration was observed for 8 (47.0 %). Only 2 eyes (11.7 %) with the best visual acuity at baseline improved. On the other hand, 17.6 % of the eyes considered separately had an improvement in their LogMar visual acuity at the end of the treatment. CONCLUSION: The results confirm the trend of Raxone® treatment to improve patients' visual acuity. Given the recommendations of a consensus conference, this treatment should be started early after the onset of LHON. It is therefore important to look for this diagnosis in the presence of any hereditary optic neuropathy, in order to be able to initiate this treatment.

[Hereditary optic neuropathies in pediatric ophthalmology]. / Neuropathies optiques héréditaires en ophtalmo-pédiatrie.

INTRODUCTION: Hereditary optic neuropathies (HON) often begin in adulthood. However, some of them can have an early onset. These may have specific clinical features and natural histories. PATIENTS AND METHODS: Retrospective study of HON patients with onset before the age of 14 years seen in a referral center. In addition to the age of onset, we evaluated the genetic etiology, visual acuity at 15 years, last best corrected visual acuity, optic disc appearance, visual field and extra-ophthalmological manifestations. RESULTS: Forty-four patients (16 women) were included; i.e. 27.8% of all patients followed for HON. The mean age of onset was 8.5±3.3 years, with an onset earlier than 3 years in 5 patients. An etiology was not found in 8 patients. Of the remaining 36 patients, 12 had Leber's hereditary optic neuropathy (LHON), 11 had dominant optic atrophy, 12 had WS/WS-like syndrome, 2 had recessive optic atrophy and 1 had spastic paraplegia type 7. For 78 eyes of 40 patients (mean age 26.9±14.5 years), the mean last visual acuity was 0.80±0.33 LogMAR, with differences according to genetic forms. Visual acuity was less than or equal to counting fingers for 7 eyes (29.1%) of 4 WS/WS-like patients and one LHON patient. CONCLUSION: Early onset NOH are not unusual. Their visual prognosis is as severe as adult onset NOH, with variations depending on the underlying genetic causes.

Ocular motility and Wilson's disease: a study on 34 patients.

BACKGROUND: Wilson's disease is an autosomal recessive genetic disorder resulting from an abnormality of copper metabolism. The excessive accumulation of copper in the brain induces an extrapyramidal syndrome. Oculomotor abnormalities occur in most extrapyramidal disorders but have rarely been studied in Wilson's disease. OBJECTIVE: To evaluate the ocular motility manifestations of Wilson's disease. METHODS: A prospective study of 34 patients affected by Wilson's disease who were recruited and their ocular motility recorded by electro-oculography (EOG). RESULTS: Vertical smooth pursuit was abnormal in 29 patients (85%). Vertical optokinetic nystagmus and horizontal smooth pursuit were impaired in 41% and 41% of patients, respectively. No MRI abnormality was found in the lenticular nuclei of seven patients who manifested ocular motility abnormalities. CONCLUSION: Vertical eye movements, in particular vertical pursuits, are impaired in Wilson's disease, more often than vertical optokinetic nystagmus and vertical saccades. EOG abnormalities can be found in patients who do not yet exhibit anatomical lesions on MRI.

Nutritional optic neuropathies.

Nutritional deficiency may be the cause of a genuine optic neuropathy, sometimes associated with involvement of the peripheral nervous system. Nutritional optic neuropathies are usually bilateral, painless, chronic, insidious and slowly progressive. Most often, they present as a non-specific retrobulbar optic neuropathy. The differential diagnosis with other causes of optic nerve involvement, in particular of toxic origin, may be particularly difficult. Nutritional deficits are often associated with toxic effects from alcohol and tobacco; therefore, the separation of the nutritional and toxic components is often illusory and artificial. The pathophysiological mechanisms involved in nutritional -- and toxic -- optic neuropathies affect biochemical pathways involved in cell energetic production, correction of oxidative stress and quenching of free radicals. The recognition of these mechanisms could provide future therapeutic alternatives. Currently, the treatment is limited to the intensive use of vitamins with variable results in individual cases, and to the implementation of preventive measures, when feasible.

[Pediatric aspects of Fabry's disease]. / Aspects pédiatriques de la maladie de Fabry.

Fabry's disease is a rare X-linked inborn error of glycosphingolipid metabolism characterised by an abnormal lipid storage due to a defect of lysozomal alphagalactosidase. The consequence is a storage of glycosphingolipides in all tissues. This storage in vessels's endothelial cells is responsible, in males, for severe ischemic lesions leading to progressive kidney failure, cardiac and cerebral dysfunctions. Similarly, it involves ocular tissues, mainly the cornea, the conjunctiva and the lens. The corneal storage, known as cornea verticillata, is a clinical marker easy to recognize by slit lamp examination of the affected males and carrier females. The enzymatic activity of alphagalactosidase is reduced in tears. Characteristic lamellar bodies can be observed by electron microscopy study of a conjunctival biopsy. Until recently, treatment was limited to symptomatic management of pain, and end-stage complications of renal failure, cardiac or brain disease. Recent studies have demonstrated that enzyme replacement therapy by genetic engineering is now shown to be promising for affected patients.

[Painful ophthalmoplegia in children: Tolosa-Hunt syndrome or ophthalmoplegic migraine?]. / Les ophtalmoplégies douloureuses de l'enfant: place du syndrome de Tolosa-Hunt et de la migraine ophtalmoplégique.

In children with painful ophthalmoplegia, the diagnosis of Tolosa-Hunt syndrome or of ophthalmoplegic migraine should only be considered when tumoral, infectious, inflammatory or vascular causes have been excluded by appropriate investigations. Both entities are classified as "neuralgia" by the International Headache Society, and seem to share a similar pathogenic mechanism. Both diseases have many clinical similarities with slight differences concerning pain characteristics or ocular associated symptoms. High resolution CT scan or contrast enhanced MRI can be necessary to exclude other causes of painful ophthalmoplegia. They can sometimes objectify an inflammatory process of the cavernous sinus in Tolosa-Hunt syndrome or a reversible enhancement and thickening of the cisternal segment of the oculomotor nerve during an ophthalmoplegic migraine. Pain and ophthalmoplegia quickly resolve with corticosteroids. Such treatment may decrease the risk of recurrence. It is important to follow-up these patients for a 2 years period and to repeat the etiologic assessment. We report here 2 cases of children with painful ophtalmoplegia.

Prolongation of latency of horizontal saccades in elderly is distance and task specific.

The present study examined horizontal saccades in healthy subjects: 9 adults (20-32 years) and 10 aged subjects (63-83 years), under gap (fixation target extinguishes prior to target onset) and overlap (fixation stays on after target onset). The gap paradigm is known to promote fast initiation of saccades while the overlap paradigm promotes voluntary saccades with longer latency. In real life we perform saccades at various distances. In this study each paradigm was run at three viewing distances-20, 40 and 150 cm, corresponding to a convergence angle of 17.1 degrees, 8.6 degrees and 2.3 degrees, respectively. Eye movements were recorded with the Chronos video eye tracker or with the photoelectric IRIS. The main findings are: (i) increase in latency of saccades with age, with distance and with the overlap condition; (ii) evidence for interaction between these factors, indicating the following anomaly: in the gap condition and at near, aged subjects show short latencies similar to those of young adults; (iii) express type of latencies (between 80 and 120 ms) occur most frequently at near in the gap condition and at similar rates in young (25%) and aged subjects (20%). The specificity of close distance combined with the gap for triggering short latency saccades could be related to both attention and oculomotor fixation disengagement. The strength of coupling between fixation-eye movement control and visual attention control varies for different locations in space, and its decline with aging can be also different.

[Spinal infarction in the anterior spinal territory with possible relation with bilharziasis]. / Infarctus médullaire dans le territoire spinal antérieur en rapport possible avec une bilharziose.

We report a case of spinal cord infarction in the anterior spinal artery territory with selective involvement of the anterior horns. A 35-year-old Mauritanian woman was hospitalized because of an acute and severe flaccid paraplegia without any sphincter dysfunction or sensory disturbance. MRI abnormalities (hypersignal on T2-weighted sequences) were restricted to the anterior horns of the lower thoracic spinal cord and conus medullaris. Adamkiewicz's artery appeared abnormally thin at arteriography. The infarction was probably related to vasculitis of schistosomal origin.

[Orbital myositis, recurrence of Whipple's disease]. / Myosite orbitaire, récidive d'une maladie de Whipple.

Whipple's disease, a chronic systemic and multi-organ disease can be associated with ophthalmological manifestations with or without CNS involvement. Myositis rarely occurs during Whipple's disease. Antibiotic treatment prevents CNS recurrence. We report here the association of an orbital pseudotumor with Whipple's disease. This myositis was discovered on a follow-up CT examination. It appeared only one year after the end of a long course of antibiotic treatment, but it resolved within a few weeks when treatment was reintroduced. Relations between these two diseases are discussed.

[Excimer laser photorefactive keratectomy retreatment following photokeratectomy under-correction]. / Retraitement à l'aide du laser excimer de surface des sous-corrections dans les suites de photokératectomies réfractives.

PURPOSE: Results of excimer laser photorefractive keratectomy are well accepted for the correction of low to moderate myopia. However, the occurrence of a regression is still a frequent complication. The purpose of the present study is to evaluate the interest and risk of excimer photorefractive keratectomy retreatment of eyes that underwent a regression of the refractive effect. PATIENTS AND METHODS: A retreatment was achieved in 27 eyes of 22 patients. This reshaping was required because of either an expected undercorrected initial treatment, either a regression of the refractive effect of the first photorefractive keratectomy that did not respond to the topical steroid therapy. As we used two different types of excimer laser to achieve the retreatments, we formed two subgroups. In the first sub-group, 13 eyes were retreated with an Excimed (Summit), and in the second one, that included 14 eyes, a laser EC5000 (Nidek) was used. The delay between the first procedure and the retreatment was 16.38 +/- 7.56 months in the first sub-group and 29.85 +/- 13.09 months in second one. The mean attempted correction for the reshaping was -3.01 +/- 1.25 diopters in the first sub-group and -1.63 +/- 0.80 diopters in the second one. RESULTS: No specifical problem was encountered during the retreatment. Specifically, we did not observe any decentring. By the third post-operative month, patients recovered a mean uncorrected visual acuity of nearly 7/10 in both sub-groups. This mean uncorrected visual acuity did not regressed during the follow-up. In addition, the mean post-operative refraction was 0.11 +/- 0.78 diopters in the first sub-group and -0.20 +/- 0.59 diopters in the second, three months after reshaping. The final refraction was -0.15 +/- 0.30 dioptres in the first sub-group and -0.70 +/- 0.62 dioptres in the second one. Nine eyes exerienced a regression during the follow-up period, from which three responded to the topical steroids. These regressions occurred in 4 eyes from the first sub-group and 5 of the second one. No other complication were observed. DISCUSSION: Although there is a aggreement about the efficacy of excimer laser in the treatment of low or moderate myopia, regressions of the refractive effect is not unfrequent. It can warrant a reshapping. Our results demonstrate the simplicity and the predictive value of excimer laser in the retreatment of these regressions after photorefractive keratectomy. This method seems more accurate than radial keratotomy. CONCLUSION: Excimer laser retreatment is highly effective in the correction of undercorrection after a previous procedure of photorefractive keratectomy, especially when the attempted correction of the initial treatment was under -6 diopters.

[Value of cerebral mapping in the study of amblyopia]. / Intérêt de la cartographie cérébrale dans l'étude de l'amblyopie.

The Alpha attenuation response to a visual stimulation was studied by quantified electroencephalogram for three posterior electrodes 01, 02, Pz, in twenty-five patients presenting either functional, deprived or cured amblyopia. A sample group allows the comparison of differences of visual attenuation responses with or without penalisation on the normal eye. The decreased percentage of cerebral activity during visual stimulations, in the Alpha band of cerebral frequencies represents the visual reactivity. Cerebral activity was checked during different sequences and visual reactivity was calculated. It demonstrates that the stimulation of the amblyopic eye shows a visual Alpha attenuation response only slightly more significant than the one obtained by stimulation of the healthy or normalised eye, or the stimulation of both eyes at the same time. But there is no change of visual Alpha attenuation when a +15 diopters penalisation is used as an optical correction for the normal eye. These findings allow us to disregard either deficient visual acuity or monocular stimulation as a cause of this phenomenon and seems to suggest a cortical neutralization as its origin. This technique could possibly objectify the therapeutic improvements during the treatment. These facts are in accordance with the neurophysiological studies of Hubel and Wiesel.

[Benign childhood intracranial hypertension]. / L'hypertension intracrânienne bénigne de l'enfant.

INTRODUCTION: Infrequent in children, benign intracranial hypertension (or pseudotumor cerebri) is most often observed in adults. Careful diagnosis requires eliminating all the other etiologies of intracranial hypertension. Most often medical, its treatment must be rapid to avoid permanent visual loss. However, a surgical procedure is necessary when vision is threatened. We present our experience with this pathology and discuss its clinical aspects, its etiologies, and the physiopathological mechanisms. PATIENTS AND METHODS: We conducted a retrospective study on children who presented benign intracranial hypertension confirmed by neuroradiological and neurosurgical examinations. These examinations also served to specify the responsible etiologies. The ophthalmologic examinations, adapted to the child's age and clinical status, included visual acuity testing, optic disc evaluation, ocular motility testing, and visual field evaluation. Progression of visual acuity and the topic disc was analyzed after treatment. RESULTS: The diagnosis of benign intracranial hypertension was confirmed in 22 children (12 boys and 10 girls). Clinical presentation included headache and visual disturbance such as visual loss and oculomotor nerve palsy. Papilledema was present in nearly all cases. Medical treatment was successful in 7 children; however, the remaining 15 patients required a lumboperitoneal shunt because of elevated intracranial pressure, no response to the medical therapy, or threatened vision. DISCUSSION: The physiopathological mechanisms of benign intracranial hypertension, an uncommon condition in children, are still unclear. It can be associated with severe visual loss. All other intracranial or medullary expansive lesions should be eliminated before diagnosis. The causes of this syndrome are not the same for pediatric and adult patients. Although medical therapy is usually sufficient to normalize the intracranial pressure, a lumboperitoneal shunt is at times required. The role of the ophthalmologist is important in detecting a possible visual loss or papilla abnormality and in ensuring proper treatment follow-up. CONCLUSION: Ophtalmologists are involved in the detection of pseudotumor cerebri and the monitoring of visual function, an important element in evaluating treatment efficacy.

[Leber's optic neuropathy]. / Neuropathie optique de Leber.

Leber hereditary optic neuropathy is associated to mutations of the mitochondrial DNA that seem to be pathogenic of this disease. However, other genetic or environmental factors must play a role in the development of this optic atrophy. Leber hereditary optic neuropathy is usually isolated. Its typical clinical feature includes in a young man a sudden and severe decrease of vision of one eye. The second eye is affected few weeks later. But, atypical feature can be observed. Thus, this diagnosis must be suspected as soon as there is no evident aetiology for an optic neuropathy, whatever the clinical feature, the age or the sex of the patient can be. There is no treatment. But visual recovery can spontaneously occurred even years after the disease appearance.