I. Ingster-Moati

The cannabinoid system and visual processing: A review on experimental findings and clinical presumptions

Cannabis is one of the most prevalent drugs used worldwide. Regular cannabis use is associated with impairments in highly integrative cognitive functions such as memory, attention and executive functions. To date, the cerebral mechanisms of these deficits are still poorly understood. Studying the processing of visual information may offer an innovative and relevant approach to evaluate the cerebral impact of exogenous cannabinoids on the human brain. Furthermore, this knowledge is required to understand the impact of cannabis intake in everyday life, and especially in car drivers. Here we review the role of the endocannabinoids in the functioning of the visual system and the potential involvement of cannabis use in visual dysfunctions. This review describes the presence of the endocannabinoids in the critical stages of visual information processing, and their role in the modulation of visual neurotransmission and visual synaptic plasticity, thereby enabling them to alter the transmission of the visual signal. We also review several induced visual changes, together with experimental dysfunctions reported in cannabis users. In the discussion, we consider these results in relation to the existing literature. We argue for more involvement of public health research in the study of visual function in cannabis users, especially because cannabis use is implicated in driving impairments.

Surveillance ophtalmologique des patients sous APS au long cours : analyse d’une population de 925 patients

But La toxicite des anti-paludeens de synthese (APS), hydroxychloroquine et chloroquine, est bien connue. Elle se traduit par une maculopathie bilaterale et irreversible. Sa prevention est une necessite. Elle repose sur l’examen ophtalmologique clinique et para-clinique comprenant champ visuel (CV), vision des couleurs (VC), electro-retinogramme (ERG) et electro-oculogramme (EOG). Le but de cette etude a ete d’analyser, dans le cadre de la prevention de la retinopathie, une serie de patients sous APS au long cours. Materiel et methodes Neuf cent vingt-cinq patients ont ete suivis entre 1995 et 1998 dans notre laboratoire : 78 % de femmes pour 22 % d’hommes. Tous les patients ont rempli une fiche de suivi de 13 items et ont beneficie d’un ERG. Resultats Quarante-huit pour cent des patients sont atteints de polyarthrite rhumatoide (PR), 29 % de lupus (L), 1 % de PR et lupus associe, 3 % de sarcoidose et 19 % de pathologie autre. La duree du traitement de moins d’un an pour 29 % des patients, de 1 a 10 ans pour 73 % et de plus de 10 ans pour 8 %. Aucune intoxication retinienne n’a ete retrouvee mais 3 % des patients ont presente une intoxication au stade pre-clinique (IPC) ou une pre-maculopathie definie par une alteration des examens para-cliniques. L’analyse statistique a montre des correlations statistiquement significatives entre l’IPC et la duree du traitement (p Conclusions Cette etude montre l’interet de l’ERG couple aux autres examens (CV, VC et EOG) dans le depistage precoce de l’IPC. Elle confirme que la dose cumulee est plus dangereuse que la dose journaliere. Enfin, elle souligne la necessite d’etudes prospectives dans chaque categorie de patients, selon en particulier leur âge et leur dose cumulee, afin de determiner pour chacun d’entre eux le meilleur examen para-clinique et le rythme de surveillance optimale.

Vertical and horizontal smooth pursuit eye movements in children: A neuro-developmental study

An evaluation of eye movements is very useful in neurological disorders but is complicated by issues such as maturation and lack of normative data in children. In order to address these issues we studied smooth pursuit eye movements of 65 normal children aged 7-11 years old. The gain of horizontal smooth pursuit (HSP) was higher than the gain of the vertical smooth pursuit (SP) and this difference had a statistical tendency to disappear with aging from 7 to 11 years. These data suggest that, in the cerebral regions involved in the control of SP, i.e. posterior parietal and superior temporal lobe regions, the networks for VSP mature latter than those for HSP.

Protocole de surveillance ophtalmologique des patients traités par antipaludéens de synthèse ou par vigabatrin au long cours

Treatment with the antimalarials chloroquine or hydroxychloroquine rarely causes retinopathy. Chloroquine and hydroxychloroquine toxicity are untreatable and can progress to legal blindness. Since 1957, there has been a consensus on the need to monitor patients on long-term chloroquine or hydroxychloroquine therapy. Currently, the procedure for follow-up includes collection of patient information, complete ophthalmological exam with automated central perimetry, and retinal electrophysiology. Screening should take place before treatment or no more than 6 months after initiation of antimalarial therapy. During treatment, monitoring relative to the baseline should be at a frequency determined by whether there are risk factors for development of toxicity, such as a cumulative dose greater than 1.8 kg, a daily dose greater than 6.5mg of hydroxychloroquine/kg/day, concurrent or past ophthalmological diseases, hepatic or renal insufficiency, age older than 65 years, and chloroquine intake. Retinopathy can occur in the absence of risk factors. The risk/benefit ratio favors therapy despite the time and expense of screening. Vigabatrin (VGB) is an effective drug for treatment of epilepsy and has been used in the treatment of West syndrome and epilepsy resistant to other drugs. VGB treatment improves quality of life, but it can induce characteristic bilateral nasal visual field defects and changes in retinal electrophysiology. Currently, the recommended procedure is to screen these patients before treatment, if possible, with a complete ophthalmological exam including perimetry and retinal electrophysiology every 6 months. It may be necessary to rely on retinal electrophysiology since some patients may not be able to undergo perimetry. The risk/benefit ratio sill clearly favors VGB treatment. Patients whose seizure incidence is reduced and have only minimal visual changes could continue VGB with strict monitoring. The others must discontinue VGB.

Visual neurophysiological dysfunction in infants exposed to hydroxychloroquine in utero.

Sir, We read with interest the report by Renault et al. on visual neurophysiological dysfunctions in infants exposed to hydroxychloroquine (HCQ) in utero (1). Indeed, data on that topic are scare and further studies are needed. However, major concerns arise regarding the methodology used. Mesopic ERG is not recommended by the International Society of Electrophysiology for Vision (ISCEV) and should not be used. ISCEV guidelines include only scotopic and photopic ERG (2). The authors have compared their results with control groups tested in 1996 for the ERG and in 1977 for the VEP. Thus, the authors had to mention that their techniques are the same as those of the earlier studies and that the flash intensity has been controlled and did not change during this period. Because, if the intensity of the flash had changed, the amplitude of the ERG would have also changed and could simply explain that there is a statistical difference between the infants tested in 2009 and those tested in 1996. With regard to the results, some infants in the study were premature. The authors stated in their previous study ‘the amplitude of these waves increased considerably throughout the period studied’ meaning during first years of life. Many electrophysiologists have concerns regarding the validity of flash-ERG in very young children and consider that abnormal results should be interpreted with caution and should be confirmed by an additional method. Furthermore, the authors say, ‘in order to avoid introducing the bias of maturity, not any ERG and VEP was carried out before the corrected age of 40 weeks’. This does not eliminate the possibility that any abnormalities found were the consequences of prematurity (3). The authors write, ‘statistically, duration of pregnancy – exposition to HCQ – was 38.6 weeks for infants with normal ERG vs 35.6 weeks for infants with abnormal ERG (Mann–Whitney test, p = 0.003). Mean corrected age at first ERG recording was not significantly different in infants with normal ERG (382 days) from infants with abnormal ERG (350 days) (Mann–Whitney test, p = 0.15)’. We understand that infants with abnormal ERG were probably premature (explaining the lower exposure to HCQ). In addition, infants with abnormal ERG were younger, and it has been established by the authors that the amplitude of the aand b-waves increases considerably with age (ref 9). As both their mothers’ diseases and then prematurity may affect foetuses, a control group must be carefully defined and should include pregnant patients with connective tissue diseases, but without HCQ treatment. Moreover, the analysis should be blind. In conclusion, significant discrepancies between the present study in which a quarter of the infants have abnormal results and previous published studies with much more reassuring data and robust methodology are probably explained by the faultiness of the method used. This is important in view of the fears that will result from these results and, thus, of their clinical consequences, i.e. increased risk of SLE flare, if HCQ is no longer given to pregnant patients (4).

Rétinopathie à l'interféron-α associé à la ribavirine atteinte de l'électro-oculogramme: à propos d'un cas

AIM Ophthalmological complications with interferon alpha (INF-alpha) have been described since 1992: toxic retinopathy with cotton-wool spots, retinal hemorrhages, visual evoked potential (VEP) modifications and visual field abnormalities. MATERIAL AND METHOD In 2002, a 44-year-old woman was referred complaining of visual problems. In 1986, she had been diagnosed with chronic hepatitis C and underwent INF-alpha therapy for 6 months with no ophthalmological symptoms. In 2001, she began a second course of INF-alpha therapy along with ribavirin. After 5 months, in February 2002, she developed hypothyroidism induced by INF, received levothyroxine and her treatment for the hepatitis C was stopped. One month later, in March, she complained of visual difficulties in dim light. Clinical ophthalmological examination and Goldmann visual field testing, electroretinogram (ERG) and visual evoked potentials (VEP) were normal but the electro-oculogram (EOG) showed that the light-peak-to-dark-trough ratios were very low: 148% in the right eye, 156% in the left eye. The fluorescein angiography was normal. The patient was followed up 4 months later, in June 2002 (after 5 months without INF-alpha therapy), showing a slight improvement of the EOG and no visual symptoms. Two other follow-up examinations were done in September 2002 and January 2003: the slight improvement persisted but the EOGs remain below the normal range values. DISCUSSION AND CONCLUSION A review of the literature brought out that an EOG is not usually done in the monitoring of patients taking INF-alpha, but we decided to do this examination because of her symptoms, the first case to our knowledge in a patient taking INF-alpha. This case report underlines the necessity of an EOG on patients with INF-alpha therapy. Until now, the pathogenesis of this retinal toxicity has been poorly understood. These results show that the retinal pigmented epithelium is probably implicated at an early stage in this retinal toxicity.But Les complications ophtalmologiques de l’interferon-α (INFα) sont connues depuis 1972 : retinopathie avec nodules cotonneux, hemorragies retiniennes, modifications des PEV et alterations du champ visuel. Materiel et methode En 2002, une patiente, âgee de 44 ans, nous a ete adressee pour une gene visuelle a l’obscurite et a l’eblouissement. En 1986, le diagnostic d’hepatite C chronique a ete porte et un traitement par INFα a ete instaure pour une duree de 6 mois. En septembre 2001, une 2 e cure est entreprise, cette fois-ci, associee a la ribavirine. Cinq mois plus tard, en fevrier 2002, le traitement est interrompu car il a induit une hypothyroidie (rapidement traitee) et des troubles visuels. En mars 2002, un examen clinique ophtalmologique complet ainsi qu’un champ visuel et un bilan electrophysiologique ont ete pratiques. Resultats Le bilan ophtalmologique clinique ainsi que le champ visuel, l’ERG et les PEV sont normaux, en revanche l’EOG est plat. L’angiographie a la fluoresceine est normale. La patiente a ete revue en juin 2002, c’est-a-dire apres 5 mois d’arret du traitement. L’EOG s’est legerement ameliore et la gene fonctionnelle a disparu. Deux autres bilans ont ete effectues l’un en septembre 2002 et le dernier en janvier 2003 qui montrent un maintien de l’amelioration mais sans retour a la normale. Discussion et conclusions L’EOG n’est habituellement pas etudie dans la retinopathie a INF-α. D’autre part, la pathogenie de cette intoxication n’est actuellement pas connue. Le fait que l’EOG de cette patiente soit tres altere, alors que son ERG est normal, temoigne d’une atteinte fonctionnelle importante du couplage entre la neuro-retine et l’epithelium pigmente. Ceci pourrait etre relie a la pathogenie de cette retinopathie toxique. Nous suggerons de pratiquer un EOG dans la prevention des retinopathies a l’INFα.

Influence de la variation de la posologie d'hydroxychloroquine (Plaquénil®) sur l'électrorétinogramme

Introduction L’electroretinogramme (ERG) est actuellement avec le champ visuel central, la vision des couleurs et l’electro-oculogramme, et avant la mise en place de nouvelles techniques, un examen de prevention de la maculopathie iatrogene aux anti-paludeens de synthese (APS). Le but de cette etude a ete de rechercher l’influence des modifications de la posologie de l’hydroxychloroquine (HCQ, Plaquenil ® sur l’ERG. Materiel et methodes Trente-deux patients sous HCQ au long cours ont ete suivis. Chaque patient a beneficie d’un examen clinique ophtalmologique et d’un bilan para-clinique comprenant au moins un ERG. Ces patients ont eu un arret ou une diminution de la posologie d’HCQ. Un 2 e ERG apres changement de posologie a ete enregistre. Les parametres de l’ERG ont ete compares avant et apres modification de la posologie. Resultats La comparaison des ERG a permis de mettre en evidence une augmentation statistiquement tres significative des amplitudes de l’onde « b » de l’ERG apres diminution de la posologie d’HCQ. Discussion et Conclusion Cette etude est, a notre connaissance, la premiere a montrer statistiquement la sensibilite de l’onde « b » de l’ERG a la variation de la posologie de l’HCQ. L’amplitude et le temps de culmination de l’onde « b » de l’ERG sont des parametres importants a surveiller lors de la prise au long cours d’HCQ. Une diminution de l’amplitude de l’onde « b » de plus de 20 % avec une augmentation du temps de culmination de cette onde chez un patient teste dans les memes conditions est un signe d’alerte, imposant la pratique des autres explorations fonctionnelles visuelles (si celles-ci n’ont pas deja ete effectuees) et une diminution voire un arret temporaire de l’HCQ. L’ERG, examen objectif, ne necessitant pratiquement aucune participation du patient, est un test utile dans la prevention de la maculopathie aux APS a condition d’etre interprete en effectuant une comparaison precise des ERG successifs chez un meme patient.

Transient retinal dysfunctions after acute cannabis use

Although cannabis is very widespread worldwide, the impact of cannabis on visual function remains poorly understood. This is partly due to numerous difficulties met in developing clinical studies in cannabis users. Here, we report the first documented case of neuroretinal dysfunction after acute cannabis smoking. This observation was favored by the need of an annual ophthalmic evaluation in the context of a chloroquine intake for a systemic lupus erythematosus in a 47-year-old heavy cannabis user. A complete ophthalmic evaluation including visual acuity tests, intraocular pressure, fundoscopic examination, automated 10° central visual field, full-field electroretinogram (ERG) and multifocal ERG was performed twice - 30 min and 5 h after cannabis smoking. A strong decrease (up to 48%) in the a-wave amplitude of the full-field ERG was measured 30 min after cannabis smoking for all scotopic responses compared with the responses 5 h after smoking. Other tests showed reproducible results between the 2 series of measurements. This clinical case suggests that acute inhalation of cannabis affects the photoreceptors functioning. This rare situation suggests further investigations are required on the impact of cannabis on retinal processing, especially since cannabis has been incriminated in car injuries.

Erratum. Sulfonylurea Therapy Benefits Neurological and Psychomotor Functions in Patients With Neonatal Diabetes Owing to Potassium Channel Mutations. Diabetes Care 2015;38:2033–2041

The online version reflects these changes. Mutations n of patients; patient no. KCNJ11 G228A n 5 1; 13 E227K n 5 1; 14 E292G n 5 1; 10 H186D n 5 1; 5 I182T n 5 1; 9 Q51G n 5 1; 8 R201C n 5 2; 16, 18 R201H n 5 7; 1, 2, 3, 7, 11, 15, 17 V59M n 5 1; 12 ABCC8 R1183W n 5 1; 4 R1380H n 5 1; 6 Jacques Beltrand, Caroline Elie, Kanetee Busiah, Emmanuel Fournier, Nathalie Boddaert, Nadia Bahi-Buisson, Miriam Vera, Emmanuel Bui-Quoc, Isabelle Ingster-Moati, Marianne Berdugo, Albane Simon, Claire Gozalo, Zoubir Djerada, Isabelle Flechtner, Jean-Marc Treluyer, Raphael Scharfmann, Helene Cavé, Laurence Vaivre-Douret, and Michel Polak, on behalf of the GlidKir Study Group Diabetes Care Volume 39, January 2016 175

Rétinopathie à l’interféron-α associé à la ribavirine : atteinte de l’électro-oculogramme

AIM Ophthalmological complications with interferon alpha (INF-alpha) have been described since 1992: toxic retinopathy with cotton-wool spots, retinal hemorrhages, visual evoked potential (VEP) modifications and visual field abnormalities. MATERIAL AND METHOD In 2002, a 44-year-old woman was referred complaining of visual problems. In 1986, she had been diagnosed with chronic hepatitis C and underwent INF-alpha therapy for 6 months with no ophthalmological symptoms. In 2001, she began a second course of INF-alpha therapy along with ribavirin. After 5 months, in February 2002, she developed hypothyroidism induced by INF, received levothyroxine and her treatment for the hepatitis C was stopped. One month later, in March, she complained of visual difficulties in dim light. Clinical ophthalmological examination and Goldmann visual field testing, electroretinogram (ERG) and visual evoked potentials (VEP) were normal but the electro-oculogram (EOG) showed that the light-peak-to-dark-trough ratios were very low: 148% in the right eye, 156% in the left eye. The fluorescein angiography was normal. The patient was followed up 4 months later, in June 2002 (after 5 months without INF-alpha therapy), showing a slight improvement of the EOG and no visual symptoms. Two other follow-up examinations were done in September 2002 and January 2003: the slight improvement persisted but the EOGs remain below the normal range values. DISCUSSION AND CONCLUSION A review of the literature brought out that an EOG is not usually done in the monitoring of patients taking INF-alpha, but we decided to do this examination because of her symptoms, the first case to our knowledge in a patient taking INF-alpha. This case report underlines the necessity of an EOG on patients with INF-alpha therapy. Until now, the pathogenesis of this retinal toxicity has been poorly understood. These results show that the retinal pigmented epithelium is probably implicated at an early stage in this retinal toxicity.But Les complications ophtalmologiques de l’interferon-α (INFα) sont connues depuis 1972 : retinopathie avec nodules cotonneux, hemorragies retiniennes, modifications des PEV et alterations du champ visuel. Materiel et methode En 2002, une patiente, âgee de 44 ans, nous a ete adressee pour une gene visuelle a l’obscurite et a l’eblouissement. En 1986, le diagnostic d’hepatite C chronique a ete porte et un traitement par INFα a ete instaure pour une duree de 6 mois. En septembre 2001, une 2 e cure est entreprise, cette fois-ci, associee a la ribavirine. Cinq mois plus tard, en fevrier 2002, le traitement est interrompu car il a induit une hypothyroidie (rapidement traitee) et des troubles visuels. En mars 2002, un examen clinique ophtalmologique complet ainsi qu’un champ visuel et un bilan electrophysiologique ont ete pratiques. Resultats Le bilan ophtalmologique clinique ainsi que le champ visuel, l’ERG et les PEV sont normaux, en revanche l’EOG est plat. L’angiographie a la fluoresceine est normale. La patiente a ete revue en juin 2002, c’est-a-dire apres 5 mois d’arret du traitement. L’EOG s’est legerement ameliore et la gene fonctionnelle a disparu. Deux autres bilans ont ete effectues l’un en septembre 2002 et le dernier en janvier 2003 qui montrent un maintien de l’amelioration mais sans retour a la normale. Discussion et conclusions L’EOG n’est habituellement pas etudie dans la retinopathie a INF-α. D’autre part, la pathogenie de cette intoxication n’est actuellement pas connue. Le fait que l’EOG de cette patiente soit tres altere, alors que son ERG est normal, temoigne d’une atteinte fonctionnelle importante du couplage entre la neuro-retine et l’epithelium pigmente. Ceci pourrait etre relie a la pathogenie de cette retinopathie toxique. Nous suggerons de pratiquer un EOG dans la prevention des retinopathies a l’INFα.