Outcomes and Complications in Patients With Hypermobile Ehlers-Danlos Syndrome Who Have Undergone Laser In Situ Keratomileusis Surgery.

PURPOSE: The purpose of this study was to determine the safety and outcomes of myopic laser in situ keratomileusis (LASIK) in patients who were secondarily diagnosed with hypermobile Ehlers-Danlos syndrome (EDS). METHODS: We conducted a case series study on patients with hypermobile EDS who underwent myopic LASIK surgery. Visual acuity, manifest refraction, a full dilated eye examination, biometry measurements, and Scheimpflug imaging were performed in the Wilmer outpatient clinic. RESULTS: There were 24 eyes of 12 patients included in this study. All participants were White women with a mean age of 46.58 years (SD 8.91 years). Participants were seen at an average of 13.83 years (SD 4.3 years, range 6-21 years) after undergoing LASIK. None of the patients in the series had a diagnosis of hypermobile EDS before LASIK surgery. Overall, 92% of patients were happy they got LASIK. The uncorrected distance visual acuity was 20/20 or better in 68% of eyes, and the best-corrected visual acuity was 20/20 or better in 92% of eyes. Manifest refraction was within 1 diopter of plano in 79% of patients. Dry eye symptoms were present in 83% of patients, and 46% of eyes had either punctate epithelial erosions or decreased tear break-up time. One of the 12 patients developed corneal ectasia in both eyes. CONCLUSIONS: Patients with hypermobile EDS are generally satisfied with myopic LASIK correction, with good visual acuity outcomes and low rates of myopic regression. However, the risk of corneal ectasia may prevent laser vision correction from being a viable treatment option in these patients. Further studies are needed to make a definitive recommendation.

Clinical Characteristics and Outcomes in Patients Undergoing Primary or Secondary Enucleation or Evisceration After Ocular Trauma.

PURPOSE: To investigate the frequency of primary versus secondary eye removal, frequency of enucleation versus evisceration, and characteristics and outcomes of patients undergoing these procedures after presenting with severe ocular trauma. PATIENTS AND METHODS: Retrospective chart review of patients presenting to the emergency department (ED) with severe eye trauma necessitating enucleation or evisceration between 2010 and 2018. RESULTS: There were 92 eyes from 90 patients included in our study. Twenty-seven percent of eyes underwent primary removal (n=25, 14 enucleation, 11 evisceration), while 73% of eyes underwent secondary removal (n=67, 50 enucleation, 17 evisceration). The mean patient age was 45.2 years (range 4.2-92.6); primary enucleation/evisceration patients were older on average than secondary eye removal patients [53.8 years (range 15.9-91.2) versus 42.2 years (range 4.2-91.6 years), p=0.04]. A median of 34 days passed between ED presentation and secondary enucleation/evisceration. Before undergoing secondary enucleation/evisceration, patients underwent a median of one ocular procedure (range 0-14) for various complications of trauma including orbital infection, choroidal or retinal tear or detachment, and wound dehiscence. Open globe injury repairs comprised 43 of the 92 total procedures (47%) performed prior to secondary enucleation/evisceration. Secondary enucleations/eviscerations required a median of seven clinic visits compared to two clinic visits required after primary surgeries (p<0.01). 10.7% of all patients (n=10) had at least one implant-related complication following enucleation/evisceration, with all but one of these patients being in the secondary enucleation/evisceration group. CONCLUSION: Primary enucleation or evisceration was performed in 27% of all eye removals, and enucleation was performed in 69.6% of all eye removals. Future research is warranted to determine if primary eye removal may be appropriate and when to consider enucleation versus evisceration.

Childhood glaucoma genes and phenotypes: Focus on FOXC1 mutations causing anterior segment dysgenesis and hearing loss.

Childhood glaucoma is an important cause of blindness world-wide. Eleven genes are currently known to cause inherited forms of glaucoma with onset before age 20. While all the early-onset glaucoma genes cause severe disease, considerable phenotypic variability is observed among mutations carriers. In particular, FOXC1 genetic variants are associated with a broad range of phenotypes including multiple forms of glaucoma and also systemic abnormalities, especially hearing loss. FOXC1 is a member of the forkhead family of transcription factors and is involved in neural crest development necessary for formation of anterior eye structures and also pharyngeal arches that form the middle ear bones. In this study we review the clinical phenotypes reported for known FOXC1 mutations and show that mutations in patients with reported ocular anterior segment abnormalities and hearing loss primarily disrupt the critically important forkhead domain. These results suggest that optimal care for patients affected with anterior segment dysgenesis should include screening for FOXC1 mutations and also testing for hearing loss.

Blood-brain barrier-adapted precision medicine therapy for pediatric brain tumors.

Targeted chemotherapeutics provide a promising new treatment option in neuro-oncology. The ability of these compounds to penetrate the blood-brain barrier is crucial for their successful incorporation into patient care. "CNS Targeted Agent Prediction" (CNS-TAP) is a multi-institutional and multidisciplinary translational program established at the University of Michigan for evaluating the central nervous system (CNS) activity of targeted therapies in neuro-oncology. In this report, we present the methodology of CNS-TAP in a series of pediatric and adolescent patients with high-risk brain tumors, for which molecular profiling (academic and commercial) was sought and targeted agents were incorporated. Four of five of the patients had potential clinical benefit (partial response or stable disease greater than 6 months on therapy). We further describe the specific drug properties of each agent chosen and discuss characteristics relevant in their evaluation for therapeutic suitability. Finally, we summarize both tumor and drug characteristics that impact the ability to successfully incorporate targeted therapies into CNS malignancy management.

Eslicarbazepine Acetate: A New Improvement on a Classic Drug Family for the Treatment of Partial-Onset Seizures.

Eslicarbazepine acetate is a new anti-epileptic drug belonging to the dibenzazepine carboxamide family that is currently approved as adjunctive therapy and monotherapy for partial-onset (focal) seizures. The drug enhances slow inactivation of voltage-gated sodium channels and subsequently reduces the activity of rapidly firing neurons. Eslicarbazepine acetate has few, but some, drug-drug interactions. It is a weak enzyme inducer and it inhibits cytochrome P450 2C19, but it affects a smaller assortment of enzymes than carbamazepine. Clinical studies using eslicarbazepine acetate as adjunctive treatment or monotherapy have demonstrated its efficacy in patients with refractory or newly diagnosed focal seizures. The drug is generally well tolerated, and the most common side effects include dizziness, headache, and diplopia. One of the greatest strengths of eslicarbazepine acetate is its ability to be administered only once per day. Eslicarbazepine acetate has many advantages over older anti-epileptic drugs, and it should be strongly considered when treating patients with partial-onset epilepsy.

Integrating RNA sequencing into neuro-oncology practice.

Malignant tumors of the central nervous system (CNS) cause substantial morbidity and mortality, yet efforts to optimize chemo- and radiotherapy have largely failed to improve dismal prognoses. Over the past decade, RNA sequencing (RNA-seq) has emerged as a powerful tool to comprehensively characterize the transcriptome of CNS tumor cells in one high-throughput step, leading to improved understanding of CNS tumor biology and suggesting new routes for targeted therapies. RNA-seq has been instrumental in improving the diagnostic classification of brain tumors, characterizing oncogenic fusion genes, and shedding light on intratumor heterogeneity. Currently, RNA-seq is beginning to be incorporated into regular neuro-oncology practice in the form of precision neuro-oncology programs, which use information from tumor sequencing to guide implementation of personalized targeted therapies. These programs show great promise in improving patient outcomes for tumors where single agent trials have been ineffective. As RNA-seq is a relatively new technique, many further applications yielding new advances in CNS tumor research and management are expected in the coming years.

A novel inherited SCN1A mutation associated with GEFS+ in benign and encephalopathic epilepsy.

Generalized epilepsy with febrile seizures plus (GEFS+) is an autosomal dominant condition often caused by mutations in SCN1A that usually first manifests as childhood simple febrile seizures but may progress to a variety of afebrile generalized seizure types. Here, we describe the case of an 8-year-old boy with a novel SCN1A mutation who developed febrile seizures at 10months of age which eventually advanced to frequent afebrile tonic-clonic seizures. His condition was unresponsive to several antiepileptic drugs and the ketogenic diet, and he experienced gradual cognitive decline. The patient's father carries the same novel mutation, but he only experienced childhood simple febrile seizures. SCN1A mutations display incomplete penetrance and variable expressivity, and the resulting severity may depend on the location and type of mutation, whether the mutation was spontaneous or inherited, and the effect of modifying alleles. The identification of novel pathogenic SCN1A mutations may eventually advance therapeutic development and prognostic capabilities.

Epigenetics and Signaling Pathways in Glaucoma.

Glaucoma is the most common cause of irreversible blindness worldwide. This neurodegenerative disease becomes more prevalent with aging, but predisposing genetic and environmental factors also contribute to increased risk. Emerging evidence now suggests that epigenetics may also be involved, which provides potential new therapeutic targets. These three factors work through several pathways, including TGF-ß, MAP kinase, Rho kinase, BDNF, JNK, PI-3/Akt, PTEN, Bcl-2, Caspase, and Calcium-Calpain signaling. Together, these pathways result in the upregulation of proapoptotic gene expression, the downregulation of neuroprotective and prosurvival factors, and the generation of fibrosis at the trabecular meshwork, which may block aqueous humor drainage. Novel therapeutic agents targeting these pathway members have shown preliminary success in animal models and even human trials, demonstrating that they may eventually be used to preserve retinal neurons and vision.

Hashimoto's encephalopathy mimicking Creutzfeldt-Jakob disease.

Hashimoto's encephalopathy is a rare, imprecisely defined autoimmune neurologic syndrome associated with Hashimoto's thyroiditis that normally responds to corticosteroids. Here, we describe the case of a 55-year-old woman who presented with subacute cognitive decline and ataxia. Neoplastic, paraneoplastic, infectious, and metabolic etiologies were ruled out. Anti-TPO antibody level was markedly elevated at 966U/mL. After one month of 60mg/day of oral prednisone, she felt back to baseline and her Montreal Cognitive Assessment dramatically improved. Physicians should strongly consider this uncommon diagnosis in patients with rapid cognitive decline and no other clear etiology.

Anterior Chamber Non-Hodgkin Lymphoma of the Iris Masquerading as Uveitis-Glaucoma-Hyphema Syndrome.

PURPOSE: To report a case of iris non-Hodgkin lymphoma initially thought to be uveitis-glaucoma-hyphema (UGH) syndrome. METHODS: We reviewed the clinical, radiographic, and histopathologic findings in a patient with recurrent hyphemas and increased ocular pressure who eventually was found to have a rapidly growing iris mass. RESULTS: An 89-year-old man with a history of cataract extraction and mantle cell lymphoma developed recurrent hyphema, which was subsequently revealed to be due to an iris mass. A biopsy revealed non-Hodgkin lymphoma that could not be formally subclassified but was suspicious for mantle cell lymphoma. The tumor showed a partial response to ibrutinib. CONCLUSION: Iris lymphoma can masquerade as a cause of recurrent hyphema after cataract extraction. Ophthalmologists should be aware of this presentation, especially in patients with a history of lymphoma.

Neurodegeneration and Neuroprotection in Glaucoma.

Glaucoma is the principal cause of irreversible blindness in the world. The disease leads to progressive optic nerve degeneration with a gradual loss of retinal ganglion cells. Neurodegeneration in glaucoma extends beyond the eye into the lateral geniculate nucleus and visual cortex, and the disease even shares some characteristics with other central nervous system degenerative disorders. Glaucoma destroys neurons through oxidative stress, impairment in axonal transport, neuroinflammation, and excitotoxicity. Autophagy may promote or inhibit disease progression. Currently, lowering intraocular pressure is the only way proven to delay glaucoma advancement. However, many new therapies are being developed, including antioxidants, adenosine receptor antagonists, Rho-pathway inhibitors, stem cell therapy, and neurotrophic factors. These therapies focus on neuroprotection, and they may eventually halt glaucoma progression or reverse the process of the disease itself.

The Application of a Contact Lens Sensor in Detecting 24-Hour Intraocular Pressure-Related Patterns.

Glaucoma is one of the leading causes of blindness worldwide. Recent studies suggest that intraocular pressure (IOP) fluctuations, peaks, and rhythm are important factors in disease advancement. Yet, current glaucoma management remains hinged on single IOP measurements during clinic hours. To overcome this limitation, 24-hour IOP monitoring devices have been employed and include self-tonometry, permanent IOP, and temporary IOP monitoring. This review discusses each IOP measuring strategy and focuses on the recently FDA-approved contact lens sensor (CLS). The CLS records IOP-related ocular patterns for 24 hours continuously. Using the CLS, IOP-related parameters have been found to be associated with the rate of visual field progression in primary open-angle glaucoma, disease progression in primary angle-closure glaucoma, and various clinical variables in ocular hypertension. The CLS has been used to quantify blink rate and limbal strain and measure the circadian rhythm in a variety of disease states including normal-tension glaucoma and thyroid eye disease. The effects of various IOP-lowering interventions were also characterized using the CLS. CLS provides a unique, safe, and well-tolerated way to study IOP-related patterns in a wide range of disease states. IOP-related patterns may help identify patients most at risk for disease progression and assist with the development of tailored treatments.

Hypothermia associated with clobazam use in adult epilepsy.

Clobazam, a 1,5-benzodiazepine FDA-approved in 2011, is commonly used to treat anxiety and epilepsy. It has not associated with hypothermia until very recently, in a case report involving two pediatric patients. Here, we report the first case of hypothermia development in an adult patient with epilepsy associated with clobazam use. A couple months after starting clobazam, the patient started developing episodes of hypothermia every several weeks, with temperatures ranging from 90 °F-95 °F. Normothermia was achieved with Bair Hugger therapy. Thyroid-stimulating hormone and cortisol levels were normal, and there was no evidence of infection in most instances. After 11 total episodes of hypothermia over a year of clobazam use, the drug was discontinued. It has now been 7 months after discontinuation, and the patient has not experienced any more episodes of hypothermia. Early recognition of the link between clobazam and hypothermia may prevent avoidable Emergency Department visits and hospitalizations.

Clobazam: A Safe, Efficacious, and Newly Rediscovered Therapeutic for Epilepsy.

Clobazam is an oral 1,5-benzodiazepine used worldwide for the treatment of many types of epilepsies, although it is currently only approved for Lennox-Gastaut syndrome in the USA. This anticonvulsant and anxiolytic therapeutic has repeatedly demonstrated great efficacy and a high safety profile in refractory epilepsy as well as in a few monotherapy trials in both children and adults. Clobazam allosterically activates the GABAA receptor, and it binds less to subunits that mediate sedative effects than other benzodiazepines. It acts quickly, maintaining a therapeutic effect for a long duration due to its active metabolite, N-desmethylclobazam. Dosage is between 5 mg and 40 mg a day, depending on patient weight, efficacy, and tolerability. Efficacy tolerance has not been a problem in the best studies. Clobazam has provided many benefits to epileptic patients. It should be used by clinicians early as an adjuvant therapy in the treatment of refractory epilepsy and even considered as monotherapy in a broad spectrum of epilepsy syndromes.

Cross-fostering differentially affects ADHD-related behaviors in spontaneously hypertensive rats.

Although both genetic and non-genetic factors are known to contribute to the occurrence of Attention-Deficit Hyperactivity/Disorder (ADHD), little is known about how they impact specific symptoms. We used a cross-fostering approach with an established animal model of ADHD, the Spontaneously Hypertensive Rat strain (SHR), to test the influence of genotype and maternal behavior on ADHD-related behaviors. SHRs and their normo-active genetic relative, Wistar Kyoto rats (WKY), were cross-fostered to an unfamiliar dam of either the same or different strain. Behavioral testing took place when the rats reached adulthood. Locomotor hyperactivity was completely dependent on the strain of the offspring. In contrast, social behavior was primarily determined by the strain of the mother, while attentional orienting behavior was influenced by both the strain of the offspring and the strain of the dam. Anxiety-related behavior was influenced by an interaction between offspring and dam strain.