Impact of trametinib on the neuropsychological profile of NF1 patients.

PURPOSE: The use of trametinib in the treatment of pediatric low-grade gliomas (PLGG) and plexiform neurofibroma (PN) is being investigated in an ongoing multicenter phase II trial (NCT03363217). Preliminary data shows potential benefits with significant response in the majority of PLGG and PN and an overall good tolerance. Moreover, possible benefits of MEK inhibitor therapy on cognitive functioning in neurofibromatosis type 1 (NF1) were recently shown which supports the need for further evaluation. METHODS: Thirty-six patients with NF1 (age range 3-19 years) enrolled in the phase II study of trametinib underwent a neurocognitive assessment at inclusion and at completion of the 72-week treatment. Age-appropriate Wechsler Intelligence Scales and the Trail Making Test (for children over 8 years old) were administered at each assessment. Paired t-tests and Reliable Change Index (RCI) analyses were performed to investigate change in neurocognitive outcomes. Regression analyses were used to investigate the contribution of age and baseline score in the prediction of change. RESULTS: Stable performance on neurocognitive tests was revealed at a group-level using paired t-tests. Clinically significant improvements were however found on specific indexes of the Wechsler intelligence scales and Trail Making Test, using RCI analyses. No significant impact of age on cognitive change was evidenced. However, lower initial cognitive performance was associated with increased odds of presenting clinically significant improvements on neurocognitive outcomes. CONCLUSION: These preliminary results show a potential positive effect of trametinib on cognition in patients with NF1. We observed significant improvements in processing speed, visuo-motor and verbal abilities. This study demonstrates the importance of including neuropsychological evaluations into clinical trial when using MEK inhibitors for patients with NF1.

Long-term outcomes of type 1 retinopathy of prematurity following monotherapy with bevacizumab: a Canadian experience.

OBJECTIVE: To report long-term structural, visual, and refractive outcomes after monotherapy with intravitreal bevacizumab injection. DESIGN: Cohort retrospective chart review. PARTICIPANTS: A total of 56 premature infants with type 1 retinopathy of prematurity. METHODS: This is a chart review at 2 Canadian institutions. Inclusion criteria were single injection of 0.625 mg  intravitreal bevacizumab and minimum age at last follow-up of 3 years. Primary outcome was retinal structure. Secondary outcomes were refractive error in spherical equivalent, monocular visual acuity, strabismus, and amblyopia. RESULTS: Fifty-six infants (101 eyes) met inclusion criteria. Mean birth weight was 707 ± 178 g (range, 420-1520 g). Mean gestational age was 25.0 ± 1.3 weeks (range, 22.9-29.7 weeks). Twenty-four eyes were in zone I (24%) and 77 in zone II (76%). Mean postmenstrual age at treatment was 36.9 ± 2.1 weeks (range, 32.8-42.0 weeks). At a mean age of 5.4 ± 1.6 years (range, 3.0-8.0 years), all eyes had a favourable structural outcome with no reactivation requiring treatment. Mean monocular visual acuity was 0.29 ± 0.27 logMAR (range, 0.0-1.3 logMAR; 89 of 101 eyes). Mean spherical equivalent was -1.98 ± 4.91 D (range, -16.63 to +5.38 D; 101 of 101 eyes). Prevalence of emmetropia (>-1.0 to ≤1 D) was 43.6%; low myopia (≥1.0 to <5 D) was 17.8%; high myopia (≥5 to <8 D) was 8.9 %; very high myopia (≥8.0 D) was 12.9%; and hyperopia (>1 D) was 16.8%. Twelve children (23%) had amblyopia, and 17 (32%) developed strabismus. CONCLUSIONS: All patients demonstrated a favourable structural outcome with a single bevacizumab injection without the need for additional laser. We suggest regular monitoring following regression of acute retinopathy of prematurity as an alternative to universal, preplanned delayed prophylactic laser treatment. Future studies to evaluate other aspects of visual function are needed.

A Case of Bilateral Microphthalmia and Extensive Colobomas of the Globes Associated with a Likely Pathogenic Homozygous SIX6 Variant.

Colobomas of the globe and microphthalmia are congenital conditions that can strongly affect vision. Etiologies are varied and include embryonic and hereditary origins. We report what is, to the best of our knowledge, the first case of a SIX6 gene pathogenic variant associated with a phenotype of both bilateral microphthalmia and extensive colobomas of the globes. A 3-week-old boy presented with bilateral microphthalmia and iris, optic nerve, and chorioretinal colobomas. Genetic analysis was performed on a panel of 78 genes (microphthalmia, anophthalmia, and coloboma panel), and a homozygous likely pathogenic variant was identified in the SIX6 gene, resulting in the loss of the initiator methionine. Thus, our report expands the phenotypic spectrum of SIX6-related disorders.

Idiopathic intracranial hypertension in a pediatric transgender patient.

PURPOSE: Androgens given for gender affirmation have been implicated in the pathophysiology of idiopathic intracranial hypertension (IIH) in transgender patients. 10 cases of transgender adults with IIH have been published but this association has not been described in younger patients. Herein we describe the first case of IIH in an adolescent transgender patient. OBSERVATIONS: A 17-year-old non-obese female-to-male transgender patient on subcutaneous testosterone since age 13 presented with a two-month history of transient visual obscuration and frontal headaches. Ophthalmological examination revealed Frisen grade 2 papilledema with preserved visual function. Lumbar puncture confirmed elevated opening pressure. Papilledema resolved with oral acetazolamide and reduction of testosterone therapy. CONCLUSIONS AND IMPORTANCE: The use of cross-sex hormone therapy (CSH) for gender affirmation may increase the risk of IIH. Awareness of this association is important as the number of younger transgender patients seeking CSH is increasing significantly.

Risk Factors for Ocular Involvement in Pediatric Graft-Versus-Host Disease.

PURPOSE: To identify risk factors for ocular graft-versus-host disease (oGVHD) in children with graft-versus-host disease (GVHD). METHODS: This retrospective cohort study identified 38 children diagnosed with GVHD who underwent an ophthalmological examination. Survival to onset of oGVHD after transplant was analyzed using Kaplan-Meier analyses with log-rank tests. A multivariable Cox proportional hazards model was run for time to oGVHD using univariate risk factors. RESULTS: The average age was 10.0 ± 5.4 years at the time of transplant. Underlying illness was acute lymphoblastic leukemia in 19 (50%) and acute myeloid leukemia in 8 (21%). Nonocular GVHD organ involvement included skin (84%), lungs (16%), intestines (50%), liver (24%), and bone marrow (3%). Fifteen children (39%) had oGVHD, of which 47% were asymptomatic. oGVHD was diagnosed 601 ± 878 days after GVHD. A significant association between risk of oGVHD and diagnosis of acute lymphoblastic leukemia (P = 0.10) or acute myeloid leukemia (P = 0.08) was not found. Organ involvement associated with oGVHD included skin (P = 0.03) and lungs (P = 0.02). Survival curves were significantly influenced by GVHD organ involvement (P = 0.02), but not underlying disease (P = 0.51). The adjusted Cox regression model yielded an independent hazard ratio of 8.82 (95% CI: 1.51-51.49; P = 0.016) for the presence of concomitant GVHD involvement of skin, lungs, and another organ. CONCLUSIONS: Children with multiorgan GVHD involvement including skin and lung disease are at increased risk for oGVHD. Given the proportion of asymptomatic cases found in this series, regular eye examinations are warranted in this population.

Allgrove Syndrome: A Report of New Pathological Variants in the AAAS Gene.

PURPOSE: To report 2 novel variants in the AAAS gene consistent with the diagnosis of Allgrove syndrome. METHODS: A 12-year-old girl was referred to our clinic for progressive bilateral decrease in visual acuity. She was known for achalasia that had been surgically treated at a very early age. On examination, she was found to have dry eye disease secondary to lacrimal insufficiency. She also had anisocoria, light-near dissociation, and bilateral optic nerve atrophy. RESULTS: Neurological examination and brain magnetic resonance imaging were within normal limits. Genetic workup revealed compound heterozygosity for 2 novel variants in the AAAS gene, confirming the diagnosis of Allgrove syndrome. The patient was referred to endocrinology to screen for adrenocorticotropic hormone insufficiency. She was started on topical lubricating therapy that improved her symptoms. CONCLUSIONS: Allgrove syndrome is a rare genetic disease that is characterized by the triad of achalasia, alacrima, and adrenal insufficiency. Early diagnosis, confirmed with genetic testing, is essential to initiate an appropriate follow-up and prevent a life-threatening addisonian crisis. Report of novel mutations is important to further characterize this disease.

Central and peripheral steady-state visual evoked potentials in children with optic pathway gliomas.

PURPOSE: Treatment of optic pathway gliomas is prompted by neuroradiological evidence of tumor growth, usually associated with progressive visual loss. Despite therapy, approximately 40% will show visual deterioration. Treatment outcome is largely based on the preservation of vision. However, current visual function assessment is often unreliable in children with optic pathway gliomas who have limited collaboration. Thus, there is a need for new clinical tools to evaluate visual functions in these children. The aim of the study was to assess the value of steady-state visual evoked potentials as a tool to assess function in the central and peripheral visual fields of children with optic pathway gliomas. METHOD: Ten patients with optic pathway gliomas and 33 healthy controls (ages 3 to 18 years) were tested using steady-state visual evoked potentials. The dartboard stimulus consisted of one central circle alternating at 16 reversals/s and one peripheral hoop alternating at 14.4 reversals/s, separated by a hoop of gray space. It was presented monocularly at 30% and 96% contrasts. RESULTS: Results indicated that central signal-to-noise ratios were significantly lower in children with optic pathway gliomas compared to controls. However, no significant group difference was detected in the peripheral visual field. CONCLUSION: Steady-state visual evoked potentials could eventually be implemented in the clinical assessment and follow-up of central visual field deficits in uncooperative or nonverbal children but seem to have limited usefulness for evaluation of peripheral visual field deficits. Additional studies are needed to identify testing parameters for full visual field assessment.

Visual disorders with psychostimulants: A paediatric case report.

Methylphenidate- and amphetamine-based psychostimulants are the most common medications used to treat the symptoms of attention-deficit/hyperactivity disorder in children. Ocular side effects including dry eyes, mydriasis, accommodation disturbance, and blurry vision are listed in the product monograph but interestingly, are rarely reported in the paediatric literature. Our patient, a 9-year-old boy, presented a significant decrease in visual acuity secondary to accommodation disorder after being treated with methylphenidate hydrochloride controlled release (Biphentin) and lisdexamfetamine (Vyvanse). The unusual acute adverse effect, altered accommodation leading to a decline in visual acuity, emphasizes the importance of considering any change in vision following the introduction of psychostimulant medication as a potential adverse effect. This case highlights the importance of pharmacovigilance especially in paediatrics where data are lacking.

Ophthalmic manifestations of Gaucher disease: the most common lysosomal storage disorder.

Gaucher disease (GD) results from a deficiency of glucocerebrosidase activity and the subsequent accumulation of the enzyme's metabolites, principally glucosylsphingosine and glucosylceramide. There are three principal forms: Type I, which is the most common, is usually considered non-neuronopathic. Type II, III and IIIc manifest earlier and have neurological sequelae due to markedly reduced enzyme activity. Gaucher's can be associated with ophthalmological sequelae but these have not been systematically reviewed. We therefore performed a comprehensive literature review of all such ophthalmic abnormalities associated with the different types of Gaucher disease. We systematically searched the literature (1950 - present) for functional and structural ocular abnormalities arising in patients with Gaucher disease and found that all subtypes can be associated with ophthalmic abnormalities; these range from recently described intraocular lesions to disease involving the adnexae, peripheral nerves and brain. In summary, Gaucher can affect most parts of the eye. Rarely is it sight-threatening; some but not all manifestations are amenable to treatment, including with enzyme replacement and substrate reduction therapy. Retinal involvement is rare but patients with ocular manifestations should be monitored and treated early to reduce the risk of progression and further complications. As Gaucher disease is also associated with Parkinsons disease and may also confer an increased risk of malignancy (particularly haematological forms and melanoma), any ocular abnormalities should be fully investigated to exclude these potential underlying conditions.

Dealing with Nystagmus.

Nystagmus has a profound impact on patients visual function and social life. Infantile nystagmus (IN) is much more common than neurological nystagmus, and establishing the correct diagnosis is key in guiding the appropriate treatment paradigm. This paper attempts to demonstrate a stepwise approach in investigation and clinical evaluation, that is (often) sufficient in differentiating IN from nystagmus of neurological origin, and to uncover underlying sensory etiologies of IN. Targeted and rational uses of paraclinical exams are emphasized when they deemed necessary to complement the clinical assessment. The author's preferred surgical and non-surgical strategies to optimize vision, and improve the head posture and strabismus that can accompany nystagmus, are discussed (although without the goal of writing a complete revision on the topic).

Endophthalmitis Following Pediatric Cataract Surgery: An International Pediatric Ophthalmology and Strabismus Council Global Perspective.

PURPOSE: To compile international data on the risk factors, diagnosis, and treatment of endophthalmitis following pediatric cataract surgery. METHODS: An e-mail containing a link to an online survey was sent to all members of the American Association for Pediatric Ophthalmology and Strabismus. The questionnaire examined the incidence, risk factors, treatment, outcomes, and prophylaxis of endophthalmitis following pediatric cataract surgery around the world. RESULTS: Two hundred thirty-seven ophthalmologists answered the questionnaire. Eight ophthalmologists (3.4%) encountered 22 cases of endophthalmitis following pediatric cataract surgery during their practice. Most patients with endophthalmitis following pediatric cataract surgery were 2 to 4 years of age (36.4%). An intraocular lens was implanted in 59.1% of cases, most of which were acrylic intraocular lenses (53.8%). The main presenting symptoms were photophobia (50%) and pain (40.9%). The most common signs were conjunctival injection (36.4%) and hypopyon (31.8%). The final visual acuity was counting fingers or worse in 86% of cases. The most common cultured organism was Staphylococcus aureus (31.8%). The most common management of endophthalmitis following pediatric cataract surgery was a combination of intravitreal, systemic, and topical antibiotics (36.4%). Most ophthalmologists (68.2%) administered prophylactic intracameral antibiotic treatment during surgery and 50% used vancomycin. CONCLUSIONS: Endophthalmitis following pediatric cataract surgery is an uncommon, multifactorial complication with poor visual prognosis. Efforts directed at minimizing its risk, such as treating potential predisposing systemic conditions, improving sterilization techniques, optimizing operative conditions to reduce complications and surgery duration, and using subconjunctival and intracameral antibiotics, decrease its incidence. Early postoperative evaluation, subsequent follow-up visits, and keeping a high index of suspicion should facilitate the recognition of endophthalmitis following pediatric cataract surgery to avoid delaying treatment. [J Pediatr Ophthalmol Strabismus. 2018;55(1):23-29.].

Clinical Presentation and Outcome of Patients With Optic Pathway Glioma.

BACKGROUND: Optic pathway gliomas (OPGs) occur sporadically or in patients with neurofibromatosis type 1 (NF1). The purpose of this study was to evaluate the clinical presentation at diagnosis and at progression of patients with OPGs. METHODS: We conducted a chart review of patients with OPGs diagnosed in a single center over a period of 15 years. Demographic data including age, sex, NF1 status, clinical presentation, and outcome were collected. RESULTS: Of the 40 patients who were identified, 23 had sporadic tumors (57.5%) and 17 had NF1-related tumors (42.5%). Among the children with NF1, there was a significant overrepresentation of girls (82.3%) (P = 0.02), while among the children without NF1, there were slightly more boys (56.5%) than girls (43.5%). The presence of nystagmus was strongly associated with sporadic optic pathway gliomas. Poor visual outcome was related to tumor affecting both optic pathways, hydrocephalus at diagnosis, and optic nerve atrophy. Of the 40 patients, five died of OPG complications (12.5%) and all had sporadic tumors. CONCLUSIONS: Our cohort is one of the largest with OPGs and a detailed description of the clinical presentation both at diagnosis and at progression. We observed a significant difference between sporadic and NF1 optic pathway gliomas in terms of demographics, clinical presentation, and outcome.

Identification and functional characterization of a novel MTFMT mutation associated with selective vulnerability of the visual pathway and a mild neurological phenotype.

Mitochondrial protein synthesis is initiated by formylated tRNA-methionine, which requires the activity of MTFMT, a methionyl-tRNA formyltransferase. Mutations in MTFMT have been associated with Leigh syndrome, early-onset mitochondrial leukoencephalopathy, microcephaly, ataxia, and cardiomyopathy. We identified compound heterozygous MTFMT mutations in a patient with a mild neurological phenotype and late-onset progressive visual impairment. MRI studies documented a progressive and selective involvement of the retrochiasmatic visual pathway. MTFMT was undetectable by immunoblot analysis of patient fibroblasts, resulting in specific defects in mitochondrial protein synthesis and assembly of the oxidative phosphorylation complexes. This report expands the clinical and MRI phenotypes associated with MTFMT mutations, illustrating the complexity of genotype-phenotype relationships in mitochondrial translation disorders.

Neurodevelopmental Outcomes Following Bevacizumab Injections for Retinopathy of Prematurity.

BACKGROUND AND OBJECTIVE: Bevacizumab intravitreal injection, a vascular endothelial growth factor inhibitor, is used to treat retinopathy of prematurity (ROP). However, concerns have been raised regarding its systemic absorption and effect on developing tissues including brain. This study compared neurodevelopment at 18 months' corrected age in preterm infants of <29 weeks' gestation treated with bevacizumab versus laser ablation. METHODS: Data from the Canadian Neonatal Network and the Canadian Neonatal Follow-Up Network databases were retrospectively reviewed. Infants born at <29 weeks' in 2010-2011 with treated ROP were studied. Neurodevelopmental outcome at 18 months was assessed by using neurologic examination and the Bayley Scales of Infant and Toddler Development Third Edition. Regression analyses were performed. RESULTS: Of 125 treated infants, 27 received bevacizumab and 98 laser. The bevacizumab group, compared with laser, obtained a median Bayley Scales of Infant and Toddler Development Third Edition motor composite score of 81 (interquartile range, 70-91) versus 88 (79-97), a language composite score of 79 (65-97) versus 89 (74-97), and a cognitive score of 90 (80-100) versus 90 (85-100). Difference was detected on the motor score only (P = .02). Odds of severe neurodevelopmental disabilities (Bayley scores <70, severe cerebral palsy, hearing aids, or bilateral blindness) was 3.1 times higher (95% confidence interval: 1.2-8.4) in infants treated with bevacizumab versus laser after adjusting for gestational age, gender, maternal education, Score for Neonatal Acute Physiology-II score, bronchopulmonary dysplasia, sepsis, and severe brain injury. CONCLUSIONS: Preterm infants treated with bevacizumab versus laser had higher odds of severe neurodevelopmental disabilities. Further investigation on the long-term safety of antivascular endothelial growth factor treatment of ROP is needed.

A Highly Diverse Portrait: Heterogeneity of Neuropsychological Profiles in cblC Defect.

Cobalamin C is a rare inborn disorder of metabolism that results in multisystemic abnormalities, including progressive visual deficits. Although the cellular pathophysiology of cblC is a field of active study, little attention has been dedicated to documenting the cognitive consequences of the defect. The neuropsychological assessment of nine individuals aged between 23 months and 24 years was conducted to establish cognitive profiles. Results reveal a marked heterogeneity, with intellectual functioning ranging from extremely low to average, and cognitive difficulties (e.g., attention) evidenced even in those who are not intellectually disabled. Central nervous system abnormalities and multisystem disease are likely to be major contributing factors to the observed cognitive impairments, with the presence of visual deficits constituting an additional impediment to normal cognitive development. This study underscores the importance of conducting in-depth neuropsychological assessments in individuals with cblC, the results of which may be particularly helpful for clinical management, guidance toward rehabilitation services, and educational/vocational planning.

Joubert Syndrome in French Canadians and Identification of Mutations in CEP104.

Joubert syndrome (JBTS) is a primarily autosomal-recessive disorder characterized by a distinctive mid-hindbrain and cerebellar malformation, oculomotor apraxia, irregular breathing, developmental delay, and ataxia. JBTS is a genetically heterogeneous ciliopathy. We sought to characterize the genetic landscape associated with JBTS in the French Canadian (FC) population. We studied 43 FC JBTS subjects from 35 families by combining targeted and exome sequencing. We identified pathogenic (n = 32 families) or possibly pathogenic (n = 2 families) variants in genes previously associated with JBTS in all of these subjects, except for one. In the latter case, we found a homozygous splice-site mutation (c.735+2T>C) in CEP104. Interestingly, we identified two additional non-FC JBTS subjects with mutations in CEP104; one of these subjects harbors a maternally inherited nonsense mutation (c.496C>T [p.Arg166*]) and a de novo splice-site mutation (c.2572-2A>G), whereas the other bears a homozygous frameshift mutation (c.1328_1329insT [p.Tyr444fs*3]) in CEP104. Previous studies have shown that CEP104 moves from the mother centriole to the tip of the primary cilium during ciliogenesis. Knockdown of CEP104 in retinal pigment epithelial (RPE1) cells resulted in severe defects in ciliogenesis. These observations suggest that CEP104 acts early during cilia formation by regulating the conversion of the mother centriole into the cilia basal body. We conclude that disruption of CEP104 causes JBTS. Our study also reveals that the cause of JBTS has been elucidated in the great majority of our FC subjects (33/35 [94%] families), even though JBTS shows substantial locus and allelic heterogeneity in this population.

Bilateral congenital corneal anesthesia in a patient with SCN9A mutation, confirmed primary erythromelalgia, and paroxysmal extreme pain disorder.

The SCN9A gene codes for the sodium voltage-gated channel NaV 1.7. Gain of function mutations cause pain disorders such as primary erythromelalgia, paroxysmal extreme pain disorder, and small fiber neuropathy. Loss of function mutations lead to congenital insensitivity to pain. We report the case of a 6-year-old girl with a SCN9A mutation who presented with both gain of function and loss of function phenotypes, including congenital corneal anesthesia.