Matthieu P. Robert

Ocular manifestations of cobalamin C type methylmalonic aciduria with homocystinuria

PURPOSE To report the ocular complications of cobalamin-C type methylmalonic aciduria with homocystinuria (cblC) in a large consecutive series of patients. METHODS Medical records of patients with genetically diagnosed cblC disease from Mount Sinai Medical Center, New York, and Hôpital Necker, Paris, France, were reviewed. All patients with the diagnosis of cblC seen after January 2008 at Mount Sinai and January 1998 at Hôpital Necker were included. RESULTS A total of 9 cases are reported. Age at initial ocular examination ranged from 3.5 months to 10 years of age. All 9 patients had early-onset disease, with manifestation of disease presenting prior to 1 year of age. Two patients had definitive optic nerve pallor. All patients had retinal findings ranging from peripheral pigmentary retinal changes to central macular atrophy with Bulls eye lesions. Optical coherence tomography was performed on one child and showed retinal thinning in the area of the bulls eye lesions. Electroretinography was performed in 6 of the 9 patients, three of whom showed decreased scotopic and photopic responses. The other three patients had normal responses on electroretinography. CONCLUSIONS Ocular findings in patients with cblC are variable. All patients in the study exhibited early-onset disease and had noteworthy ophthalmic findings. To the best of our knowledge, this is the first study in the literature correlating optical coherence tomography findings with fundus findings in cblC.

Asymptomatic atrophy of the temporal median raphe of the retina associated with cerebral vasculopathy in homozygous sickle cell disease

A 13-year-old girl with homozygous sickle cell disease was referred for vision loss in her left eye of 1 years duration. Clinical findings were consistent with a past retinal arterial occlusion. In the asymptomatic right eye, spectral domain optical coherence tomography showed a severe atrophy of the inner retinal layers of the temporal median raphe; a significant internal carotid stenosis was also present. We hypothesize that specific atrophy of the retinal temporal median raphe resulted from chronic ischemia. The inner layers of the retina are vascularized by terminal vessels and the median raphe can therefore be regarded as a junction territory; its atrophy may represent an ocular equivalent of a silent border zone cerebral infarct.

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.

Shapiro-Shulman and Sturge-Weber Syndromes

To the Editor: In 1976, Shapiro and Shulman described a condition consisting of bilateral facial nevi involving the lower face and upper cervical areas, macrocrania, cephalic venous hypertension, and anomalous intracranial venous return [1]. We read with great interest the report by Prats Viñas et al. [2], who highlighted a controversial issue concerning the nature of this syndrome: is it a variant of Sturge-Weber syndrome, or a discrete entity? Based on clinical and magnetic resonance findings in one of their patients, the authors defend the second opinion. The pink vascular lesions present at birth in their patient faded slowly over time. The authors therefore concluded that these were vascular birthmarks, and not real hemangiomas. It is the rule, however, for port wine stains in true Sturge-Weber syndrome to fade over time, and in some instances to a considerable extent. The histologic nature of port wine stains in Sturge-Weber syndrome is a matter of debate. It remains unclear whether they are actual hemangiomatous tumors, or simply, as suggested by several studies, areas of capillary dilatations. Impaired cortical venous drainage and early drainage through the extracranial system are also associated with Sturge-Weber syndrome, and according to a recent hypothesis, would even be the cause of all manifestations in Sturge-Weber syndrome, with the port wine stains, ophthalmic manifestations, and leptomeningeal thickening all resulting from venous stasis in the areas depending on compensatory collateral venous channels [3]. Obviously, the clinical expressions of Shapiro-Shulman syndrome and SturgeWeber syndrome greatly differ. The case reported by Prats Viñas et al. [2] deserves attention, because the described cutaneous lesions mixed the features of both conditions. It would have been interesting to observe whether the episcleral veins were initially dilated in this child, compatible with the minimal ocular involvement in Sturge-Weber syndrome, and whether the characteristics of the meninges on magnetic resonance imaging were normal. The hypothesis of a congenital abnormality of cerebral venous drainage with both altered cortical and lower dural sinus drainage could indeed explain the whole picture. However, we are skeptical that this hypothesis would suffice from a pathophysiologic viewpoint for

Leopard spot retinopathy: an early clinical marker of leukaemia recurrence?

Dear Editor, Leopard spot retinopathy (LSR) is a very rare pigment pattern, mainly reported in leukaemia recurrence in children as part of a constellation of acute neurological signs [1, 2, 5, 7]. We report two cases of adult patients with a history of T-cell acute lymphoblastic leukaemia (ALL) in complete remission, who presented with isolated LSR several months before the diagnosis of ALL neuro-meningeal recurrence.

Relevance of Identifying JAG1 Mutations in Patients With Isolated Posterior Embryotoxon

Purpose:Although posterior embryotoxon (PE) has a high incidence in the general population, clinicians should exclude any sign of glaucoma in its presence. This anatomic abnormality is often referred to as “isolated” when the intraocular pressure is normal. Nevertheless, it may be the only sign of Alagille syndrome (AS) that can be clinically heterogenous, as presented here. This possibility must be known, to look for involvement of other organs, and in case of suspicion, mutation of the JAG1 gene must be considered. Methods:In this case series, we present the observation of a family with 3 individuals from 3 generations, in whom PE was a marker of AS. Results:PE were observed in these 3 patients and considered as “isolated” as the intraocular pressure was normal. The 2 elder patients were also followed for atypical retinal dystrophy with speckling of the retinal pigment and optic disc drusen. AS syndrome was suspected when mild liver dysfunction was detected in the youngest girl. The detection of JAG1 mutation confirmed this diagnosis. Conclusions:As AS can be clinically heterogenous, it must be considered in case of isolated PE. Involvement of other organs must be looked for to search for mutation of the JAG1 gene in relevant cases.

Ocular vestibular evoked myogenic potentials: the missing link

Stabilization of oculomotor and postural responses results from a complex multisensory integration, which can be defined as the process of matching multiple internal representations of an external event (head and trunk rotations), obtained from different sensory modalities (visual, vestibular and proprioceptive), into a single intrinsic frame of reference, in which appropriate motor commands can be coded. Several characteristics of the stabilizing synergies make them a unique model to study how sensorimotor transformations are implemented by the central nervous system. Firstly, these synergies have a purpose, which is well defined and requires the computation of an equally well-understood quantity, i.e. self-motion. Secondly, the input (velocity of the visual world detected by the eyes, velocity of the head detected by the vestibular system, etc.) as well as the static and dynamic motor responses to these inputs (eye and head movements, change in the skeletal geometry) is quantifiable with precision. Thirdly, the stabilizing synergies have been shown to display plasticity in adult humans and animals either under the pressure of environmental changes (prism adaptation, repetitive stimulation) or pathological changes (vestibular neuritis, unilateral labyrinthectomy, vestibular neurectomy). Consequently, the neural networks implementing the sensorimotor transformations underlying gaze and postural control have been intensively studied for the past sixty years and they are well described. It remains that despite its plasticity, gaze and postural stabilization can be disturbed by senescence and several pathologies; in an ageing population, vertigo, perception of instability and falls have become of great concern. Falls are the leading cause of both non-fatal and fatal injuries among the over-65 age group (Sleet et al. 2008). With that perspective, several tests were developed to probe the function of the vestibulo-ocular and vestibulo-spinal synergies, in order to detect vestibular deficits in due time. The vestibulo-ocular reflexes of semicircular canal origin can be tested by using caloric and rotatory stimuli and the head impulse test. The cervical and ocular vestibular evoked myogenic potentials (oVEMPs) are used to test the saccular and utricular functions, respectively. A common denominator of these clinical tests is that they rely for their interpretation on electrophysiological studies performed in animal models. That is, their validity relies on the fact that the activation of a given sensor and the resulting motor behaviour was demonstrated to be similar in patients and in the animal models where the neuronal vestibulo-ocular and vestibulo-spinal networks could be described. In that context, oVEMP recordings were recently proposed as a new and increasingly popular technique to clinically test otolith function (Todd et al. 2007). oVEMPs are evoked by bone-conducted sound and vibrations stimuli to probe the vestibulo-ocular pathways and are thought to result mainly from utricular stimulation (Chiarovani et al. 2011). In animal models, selective utricular nerve stimulations evoke excitatory and inhibitory responses in the contralateral superior oblique motoneuron pool and the ipsilateral inferior oblique motoneuron pool (Uchino et al. 1996). However, it remained to ascertain the muscle of origin of the oVEMP when tested in humans. This is precisely what Weber et al. (2012) elegantly succeeded in demonstrating in an article in this issue of The Journal of Physiology, by recording single motor unit activity in human extra-ocular muscles. Reviving a heroic tradition from the first days of physiology of testing on themselves a quite invasive procedure, the authors recorded their own inferior oblique (IO) and inferior rectus (IR) muscle activity with concentric needle electrodes, following bursts of 500 Hz skull vibration and sound – two otolith stimuli. After bone vibration of the midline forehead, highly synchronous excitation of the IO and the IR muscles was recorded, with a reciprocal activation pattern after a short latency. Sound stimulation of one ear produced short-latency excitation of the contralateral IO muscle. Simultaneous needle and surface recordings proved the IO to be responsible for the oVEMP. By using oVEMP to investigate eye muscle activity during the translational vestibular ocular reflex in humans, not only did Weber and colleagues (2012) confirm a crucial physiological hypothesis, they also reopened a wide field for future research, much beyond the peculiar setting of self-experimentation. Needle electromyography of extra-ocular muscles in humans has slowly declined after its golden age in the 1960s, although technical advances now allow for more refined single motor unit recordings. While this technique is less frequently used for clinical purposes in the era of molecular genetics (Finsterer 2008), it remains essential for physiological studies, as it is the only way to help bridge the many existing gaps between animal experimentation and novel clinical tests or findings.