Progressive Retinopathy in a Patient with Mucopolysaccharidosis Type II undergoing Enzyme Replacement Therapy: A Case Report.

PURPOSE: To report the changing fundus autofluorescence (FAF) and ocular coherence tomographic (OCT) findings through time in a patient with mucopolysaccharidosis type II being treated with idursulfase, an enzyme replacement therapy (ERT). METHODS: Case report with clinical photography. RESULTS: We report the case of a 27-year old male patient with mucopolysaccharidosis type II whom we followed from 2019-2023. Throughout follow-up we noticed a slow increase of parafoveal outer retinal atrophy centripetally which is reflected in a smaller hyper-auto-fluorescent ring and increasing ring scotoma on visual field testing. The patient remains asymptomatic.Discussion/Conclusion: Despite continuing long-term enzyme replacement treatment with idursulfase the retinopathy associated with mucopolysaccharidosis type II progressed in our patient.

Recurrent multiple eye muscle palsy as a first sign of sarcoidosis.

Purpose: To report a case of (neuro)sarcoidosis presenting solely with recurrent cranial nerve palsies in a 57-year-old Caucasian female. Methods: Case report with clinical imaging. Results: A 57-year-old female first presented with a right sixth nerve palsy, which resolved spontaneously after 6 months. Three years later she was diagnosed with a sixth nerve palsy in the fellow eye followed by a complete palsy of the left third cranial nerve four months after. Medical history consisted of migraine and hypercholesterolemia. Further neurological and ophthalmic work-up was unrevealing at first. After repeated magnetic resonance imaging, an enhancing lesion in the left cavernous sinus was seen, which was initially diagnosed as a meningioma. However, imaging of the chest revealed an image of sarcoidosis, and the lesion and ophthalmoplegia of the left eye disappeared with systemic corticosteroid treatment. Discussion: Sarcoidosis is the ultimate imitator and the possibility of neurosarcoidosis must be taken into account when presented with unexplained ophthalmoplegia. Neurosarcoidosis has imaging properties very similar to other diseases such as a meningioma, and misdiagnosis occurs easily. Spontaneous recovery of ophthalmoplegia can rarely occur in neurosarcoidosis.

CEP162 deficiency causes human retinal degeneration and reveals a dual role in ciliogenesis and neurogenesis.

Defects in primary or motile cilia result in a variety of human pathologies, and retinal degeneration is frequently associated with these so-called ciliopathies. We found that homozygosity for a truncating variant in CEP162, a centrosome and microtubule-associated protein required for transition zone assembly during ciliogenesis and neuronal differentiation in the retina, caused late-onset retinitis pigmentosa in 2 unrelated families. The mutant CEP162-E646R*5 protein was expressed and properly localized to the mitotic spindle, but it was missing from the basal body in primary and photoreceptor cilia. This impaired recruitment of transition zone components to the basal body and corresponded to complete loss of CEP162 function at the ciliary compartment, reflected by delayed formation of dysmorphic cilia. In contrast, shRNA knockdown of Cep162 in the developing mouse retina increased cell death, which was rescued by expression of CEP162-E646R*5, indicating that the mutant retains its role for retinal neurogenesis. Human retinal degeneration thus resulted from specific loss of the ciliary function of CEP162.

COMBINED CENTRAL RETINAL ARTERIAL AND VENOUS OCCLUSIONS DUE TO LEUKEMIC INFILTRATION.

PURPOSE: To report combined central arterial and venous occlusions secondary to bilateral leukemic interfascicular optic nerve infiltration in a 56-year-old man. This was the sole presentation of a relapse in T/myeloid mixed-phenotype acute leukemia after 5 months of remission. METHODS: Case report with clinical photography. RESULTS: A 56-year-old man reported to be in complete remission of T/myeloid mixed-phenotype acute leukemia presented with sudden painless loss of vision in his left eye. Fundoscopy showed unilateral severe optic disk swelling with characteristic findings of a central retinal vein occlusion, namely, intraretinal and preretinal hemorrhages and cotton-wool spots, as well as the features of a central retinal artery occlusion resulting in a pale, edematous retina and a characteristic cherry-red spot. Blood analysis, cerebrospinal fluid evaluation, and bone marrow analysis were performed in combination with medical imaging. No evidence of leukemic relapse was found. An optic nerve biopsy was indicated because of decompensation of the contralateral eye and ultimately confirmed leukemic infiltration. CONCLUSION: Regardless of no hematological and nonspecific imaging findings, optic nerve biopsy may be crucial for clinical decision-making in a patient with acute complete vision loss and a history of leukemia.

Lose the Nintendo and thou shall be healed! Restoring vision in malingering.

Non-organic visual loss can be hard to prove or explain to the parents of affected children at times. Here, we describe a simple yet effective approach that may help solve both issues by ensuring that the patient refrains from visual stimuli.

MITOGEN-ACTIVATED PROTEIN INHIBITORS: FULL-FIELD ELECTRORETINOGRAM DEMONSTRATING GENERALIZED RETINAL DYSFUNCTION.

PURPOSE: To report a patient with generalized retinal toxicity to mitogen-activated protein inhibitors. METHODS: Retrospective case report. RESULTS: Full-field electroretinogram findings indicate a generalized toxicity to the use of the mitogen-activated protein inhibitor trametinib. There was an improved response and resolution of serous detachments after decreasing the dose. CONCLUSION: Mitogen-activated protein inhibitors may affect global retinal function, as opposed to the serous detachments that are concentrated in the posterior pole. This may be of importance in further understanding the underlying pathologic mechanisms.

Long-Read Sequencing to Unravel Complex Structural Variants of CEP78 Leading to Cone-Rod Dystrophy and Hearing Loss.

Inactivating variants as well as a missense variant in the centrosomal CEP78 gene have been identified in autosomal recessive cone-rod dystrophy with hearing loss (CRDHL), a rare syndromic inherited retinal disease distinct from Usher syndrome. Apart from this, a complex structural variant (SV) implicating CEP78 has been reported in CRDHL. Here we aimed to expand the genetic architecture of typical CRDHL by the identification of complex SVs of the CEP78 region and characterization of their underlying mechanisms. Approaches used for the identification of the SVs are shallow whole-genome sequencing (sWGS) combined with quantitative polymerase chain reaction (PCR) and long-range PCR, or ExomeDepth analysis on whole-exome sequencing (WES) data. Targeted or whole-genome nanopore long-read sequencing (LRS) was used to delineate breakpoint junctions at the nucleotide level. For all SVs cases, the effect of the SVs on CEP78 expression was assessed using quantitative PCR on patient-derived RNA. Apart from two novel canonical CEP78 splice variants and a frameshifting single-nucleotide variant (SNV), two SVs affecting CEP78 were identified in three unrelated individuals with CRDHL: a heterozygous total gene deletion of 235 kb and a partial gene deletion of 15 kb in a heterozygous and homozygous state, respectively. Assessment of the molecular consequences of the SVs on patient's materials displayed a loss-of-function effect. Delineation and characterization of the 15-kb deletion using targeted LRS revealed the previously described complex CEP78 SV, suggestive of a recurrent genomic rearrangement. A founder haplotype was demonstrated for the latter SV in cases of Belgian and British origin, respectively. The novel 235-kb deletion was delineated using whole-genome LRS. Breakpoint analysis showed microhomology and pointed to a replication-based underlying mechanism. Moreover, data mining of bulk and single-cell human and mouse transcriptional datasets, together with CEP78 immunostaining on human retina, linked the CEP78 expression domain with its phenotypic manifestations. Overall, this study supports that the CEP78 locus is prone to distinct SVs and that SV analysis should be considered in a genetic workup of CRDHL. Finally, it demonstrated the power of sWGS and both targeted and whole-genome LRS in identifying and characterizing complex SVs in patients with ocular diseases.

Facial Pain: A Comprehensive Review and Proposal for a Pragmatic Diagnostic Approach.

BACKGROUND: Facial pain, alone or combined with other symptoms, is a frequent complaint. Moreover, it is a symptom situated at, more than any other pain condition, a crosspoint where several disciplines meet, for example, dentists; manual therapists; ophthalmologists; psychologists; and ear-nose-throat, pain, and internal medicine physicians besides neurologists and neurosurgeons. Recently, a new version of the most widely used classification system among neurologists for headache and facial pain, the International Classification of Headache Disorders, has been published. OBJECTIVE: The aims of this study were to provide an overview of the most prevalent etiologies of facial pain and to provide a generic framework for the neurologist on how to manage patients presenting with facial pain. METHODS: An overview of the different etiologies of facial pain is provided from the viewpoint of the respective clinical specialties that are confronted with facial pain. Key message: Caregivers should "think outside their own box" and refer to other disciplines when indicated. If not, a correct diagnosis can be delayed and unnecessary treatments might be given. The presented framework is aimed at excluding life- or organ-threatening diseases, providing several clinical clues and indications for technical investigations, and ultimately leading to the correct diagnosis and/or referral to other disciplines.

Central nervous system gadolinium accumulation in patients undergoing periodical contrast MRI screening for hereditary tumor syndromes.

BACKGROUND: Patients with hereditary tumor syndromes undergo periodical magnetic resonance imaging (MRI) screening with Gadolinium contrast. Gadolinium accumulation has recently been described in the central nervous system after repeated administrations. The prevalence and rate of accumulation in different subgroups of patients are unknown. Neither are the mechanism nor clinical impact. This may cause uncertainty about the screening. To explore the prevalence and rate of Gadolinium accumulation in different subgroups, we retrospectively analyzed MRIs of patients with von Hippel-Lindau disease (VHL) and Tuberous Sclerosis Complex (TSC). METHODS: We determined the prevalence and rate of accumulation in the dentate nucleus and globus pallidus on unenhanced T1-weighted MRI from VHL and TSC patients. We compared the signal intensities of these regions to the signal intensity of the pons. We evaluated the impact of number of MRIs, kidney function and liver function on Gadolinium accumulation. RESULTS: Twenty eight VHL patients and 24 TSC patients were included. The prevalence of accumulation in the dentate nucleus and globus pallidus increased linearly according to number of Gadolinium enhanced MRIs and was higher in the VHL group (100%). A significant linear correlation between number of MRIs and increased signal intensity was observed in the VHL group. CONCLUSIONS: Gadolinium accumulation occurs in almost all patients undergoing contrast MRI screening after >5 MRIs. We advocate a screening protocol for patients with hereditary tumor syndromes that minimizes the Gadolinium dose. This can be accomplished by using a single administration to simultaneously screen for brain, spine and/or abdominal lesions, using an MRI protocol focused on either VHL- or TSC-specific lesions. Higher prevalence and rate of accumulation in VHL patients may be explained by the typical vascular leakage accompanying central nervous system hemangioblastomas.

Retinal nerve fiber layer thickening in ARSACS carriers.

PURPOSE: Two Caucasian Belgian families were diagnosed with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). The ophthalmological findings in both ARSACS disease and carriers are described. METHODS: In addition to a complete ophthalmological assessment, in both patients and carriers, spectral-domain Optical Coherence Tomography scans of the peri-papillary retinal nerve fiber layer were performed. RESULTS: Molecular analysis revealed a missense mutation which has not been reported before. Besides patients with ARSACS, who also presented additional ophthalmological abnormalities i.e. eye movement problems, ARSACS carriers demonstrated thickening of the retinal nerve fiber layer. CONCLUSION: The most conspicuous ophthalmological feature of ARSACS is an increased thickness of the peri-papillary retinal nerve fiber layer. Retinal striation and thickening of the nerve fiber layer on spectral-domain Optical Coherence Tomography appeared also in carriers of the ARSACS-gene. Other ophthalmological features encountered, were gaze-evoked nystagmus and rebound nystagmus.