Improved Signs and Symptoms of Dry Eye Disease for Restasis® Patients Following a Single Tearcare® Treatment: Phase 2 of the SAHARA Study.

Purpose: To evaluate dry eye disease (DED) signs and symptoms six months after a single treatment with Localized Heat Therapy (LHT) (TearCare, Sight Sciences) for patients previously treated for six months with cyclosporine (0.05%) ophthalmic emulsion (CsA) BID (Restasis, Allergan). Setting: Nineteen ophthalmic and optometric practices in 11 US states. Design: Multicenter, cross-over, six month extension to the SAHARA randomized, controlled trial (RCT). Included patients were those randomized to CsA in Phase 1 of the SAHARA RCT. Methods: This was the second phase of the SAHARA RCT in which, following the 6-month endpoint, all patients that had been randomized to CsA discontinued CsA and were treated with LHT and subsequently followed for an additional six months. Outcome measures at 12 months for CsA patients crossed over to LHT included TBUT, OSDI and MGSS. Results: One hundred and sixty-one patients (322 eyes) were analyzed. Mean (SD) baseline TBUT prior to CsA was 4.4 (1.2) seconds, 5.6 (2.6) at 6 months which improved to 6.6 (3.2) and 6.1 (2.8) seconds (both P < 0.001) at 9 and 12 months (3, 6 months post LHT). Mean (SD) OSDI was 50.0 (14.9) at baseline and 34.2 (21.5) after CsA. With LHT at 6 months, this improved to 30.0 (20.6) and 31.0 (19.5) at 9 and 12 months (P = 0.162 vs month 6, P < 0.0001 vs baseline). MGSS was 7.1 (3.2) at baseline, 13.3 (8.2) at the end of CsA treatment which improved to 17.4 (8.8) and 16.1 (9.0) at 9 and 12 months; both P <0.001. Conclusion: SAHARA showed 6-month superiority of LHT to CsA in clinical signs and non-inferiority in symptom scores. This extension shows that patients treated with CsA for 6 months can achieve meaningful additional improvement in signs and symptoms lasting for as long as 6 months following a single LHT treatment without the need for topical prescription therapy.

A Randomized, Controlled Trial Comparing Tearcare® and Cyclosporine Ophthalmic Emulsion for the Treatment of Dry Eye Disease (SAHARA).

Purpose: We compare outcomes in eyes with dry eye disease (DED) treated with TearCare (TC) or topical cyclosporine 0.05% (RESTASIS; CsA). Setting: Nineteen ophthalmic and optometric practices in 11 US states. Design: Multicenter, randomized, assessor-masked, controlled IRB-approved trial. Eligible subjects: ≥22 years of age, dry eye symptoms within 3-6 months, Tear Break-up Time (TBUT) ≥1 to ≤7 s, Meibomian Gland Secretion Score (MGSS) ≤12, Ocular Surface Disease Index (OSDI) of 23-79. Randomized (1:1) to TC or CsA. TC subjects treated at baseline and month 5; CsA was twice daily for 6 months. Methods: Follow-up visits were scheduled for Day 1, Week 1, Months 1, 3, and 6 with primary inference at Month 6. Primary outcomes: TBUT and OSDI; secondary outcomes: MGSS, conjunctival and corneal staining, eye dryness score (EDS), symptoms assessment in dry eye (SANDE) score, and Schirmer tear score (STS). Safety assessments included adverse events, best corrected visual acuity, intraocular pressure, and slit-lamp findings. Results: Overall, 345 subjects, 172 TC and 173 CsA. TBUT improved at all time points in both groups (p<0.0001), with statistically greater improvement for TC versus CsA (p=0.0006). OSDI improved significantly at all time points in both groups (p<0.0001) with no significant differences between treatments. MGSS and other measures of meibomian gland function improved significantly more with TC eyes versus CsA; other secondary outcomes showed significant improvements in both groups with no difference between groups. Treatment-related adverse events were uncommon (10 total, 8 in the CsA group consistent with prior CsA studies); most (9/10) mild. Conclusion: TC provides statistically superior and sustained improvement in TBUT and multiple measures of meibomian gland secretion, and non-inferior improvement in OSDI, corneal and conjunctival staining, SANDE, EDS, and STS versus CsA. TC should be a preferred treatment for DED associated with MGD.

Design and Usability Study of a Point of Care mHealth App for Early Dry Eye Screening and Detection.

Significantly increased eye blink rate and partial blinks have been well documented in patients with dry eye disease (DED), a multifactorial eye disorder with few effective methods for clinical diagnosis. In this study, a point of care mHealth App named "EyeScore" was developed, utilizing blink rate and patterns as early clinical biomarkers for DED. EyeScore utilizes an iPhone for a 1-min in-app recording of eyelid movements. The use of facial landmarks, eye aspect ratio (EAR) and derivatives enabled a comprehensive analysis of video frames for the determination of eye blink rate and partial blink counts. Smartphone videos from ten DED patients and ten non-DED controls were analyzed to optimize EAR-based thresholds, with eye blink and partial blink results in excellent agreement with manual counts. Importantly, a clinically relevant algorithm for the calculation of "eye healthiness score" was created, which took into consideration eye blink rate, partial blink counts as well as other demographic and clinical risk factors for DED. This 10-point score can be conveniently measured anytime with non-invasive manners and successfully led to the identification of three individuals with DED conditions from ten non-DED controls. Thus, EyeScore can be validated as a valuable mHealth App for early DED screening, detection and treatment monitoring.

Point of care diagnosis of dry eye disease with a sensitive immunoassay for dual biomarker detection.

Dry eye disease (DED) is a multifactorial eye disease with few effective methods for clinical diagnosis and treatment. It is the most common eye disease with significant health challenges of the unprecedented aging population. Recent proteomic studies and clinical research have led to the discovery of several biologically relevant biomarkers, with increased levels of Interleukin-6 (IL-6) and decreased levels of lactoferrin being clinically validated in the progression of DED. In this study, a sensitive point of care (POC) DED diagnostic method was developed for targeting dual biomarkers of IL-6 and lactoferrin in the tear samples. A paper-based lateral flow immunoassay (LFIA) was established in a double-antibody sandwich fashion with colloid gold nanoparticles acting as probes. The minimal detection concentrations were 0.1 ng/ml and 10 ng/ml for IL-6 and lactoferrin, respectively. Separated conventional ELISA tests were also performed with data confirming results from the LFIA tests. A trial study was conducted with 20 tear samples from DED patients and healthy controls. All DED tear samples exhibited significantly higher levels of IL-6 and decreased levels of lactoferrin, as compared to the normal controls. A quantitative analysis of LFIA images was carried out using ImageJ software for an accurate data interpretation. This dual biomarker detection method is sensitive and affordable with quick turnaround time. Design of a larger clinical study in the future can further validate this POC assay for early diagnosis as well as patients' self-management of chronic states of DED.

Reliability and application variability of a commercially available infrared videonystagmography unit.

PURPOSE: Nystagmus is a condition of involuntary eye movement. The causes for nystagmus may be congenital, idiopathic, or acquired. Considerable debate exists on the therapeutic potential of various surgical techniques. Currently, there are neither standardized protocols nor devices to record quantitative data on patients with clinical nystagmus undergoing various procedures at multiple centers to facilitate randomized prospective clinical trials. METHODS: The authors evaluated the reliability and variability of a commercially available infrared videonystagmography unit by recording eye movement waveforms elicited from normal volunteers (n = 117, 13 patients, 9 trials) by different examiners (A, B, and C). Five movement characteristics were examined, including saccadic latency, velocity and precision, and pursuit gain and velocity. RESULTS: The overall test/retest variability was low, where the median coefficient of variation of the three testers for all five eye movement categories was less than 15%, and less than 10% of the coefficients of variation calculated were more than 20%. However, there was a significant difference in interobserver variability for all outcomes, except saccade latency. CONCLUSIONS: The between-tester analysis was found to have greater variability than the test/retest reliability analysis. Future studies at multiple sites using videonystagmography measurements should aim to have each patient repeatedly tested by the same tester. In anticipation of multicenter, randomized, prospective clinical trials of surgical procedures for nystagmus, standardized protocols for nystagmographic data collection and analysis must be validated both within and among participating centers.

Bilateral dacryocystoceles in a pregnant woman.

The authors describe, for the first time, bilateral, sequential large dacryocystoceles during pregnancy and review the literature for this presentation. A 26-year-old, 15-week pregnant woman presented with OD epiphora, diplopia, and pain in the setting of an inferomedial orbital mass. Surgical exploration and histopathology were consistent with a dacryocystocele, and a dacryocystorhinostomy was curative. She returned at 34-week gestation, with an identical presentation on the left side. Review of the literature reveals that dacryocystoceles occasionally present in adults; however, bilateral involvement may be unusual. Bilateral dacryocystoceles have not been previously reported in a pregnant woman.

Imaging in orbital trauma.

Orbital trauma is one of the most common reasons for ophthalmology specialty consultation in the emergency department setting. We survey the literature from 1990 to present to describe the role of computed tomography (CT), magnetic resonance imaging (MRI) and their associated angiography in some of the most commonly encountered orbital trauma conditions. CT orbit can often detect certain types of foreign bodies, lens dislocation, ruptured globe, choroidal or retinal detachments, or cavernous sinus thrombosis and thus complement a bedside ophthalmic exam that can sometimes be limited in the setting of trauma. CT remains the workhorse for acute orbital trauma owing to its rapidity and ability to delineate bony abnormalities; however MRI remains an important modality in special circumstances such as soft tissue assessment or with organic foreign bodies.

Imaging of eyelid lymphatic drainage.

PURPOSE: Traditional descriptions of lymphatic drainage show eyelids emptying into the submandibular or preauricular basin. However recent studies based on in vivo lymphatic imaging show a possible predilection for the preauricular basin. We describe lymphoscintigraphy and report findings in patients with eyelid malignancies undergoing sentinel lymph node biopsy (SLNB). METHODS: Retrospective chart review of 15 consecutive patients at a single institution with eyelid carcinoma undergoing SLNB. The primary outcome measure was primary facial lymphatic drainage site from the eyelid as determined by lymphoscintigraphy. RESULTS: The preauricular basin was the site of focal radioactive uptake in all 15 patients. The location of the primary tumor was as follows: medial upper eyelid (1), medial canthus (3), medial lower eyelid (3), lateral upper eyelid (3), and lateral lower eyelid (5). The types of tumor were: invasive squamous cell carcinoma (7), malignant melanoma (3), and sebaceous cell carcinoma (2), Merkel cell carcinoma (2), and conjunctival spindle cell carcinoma (1). CONCLUSIONS: Lymphoscintigraphy is increasingly used in the context of SLNB for periocular malignancy. The recent literature suggests that the preauricular lymph node basin may be the primary site of eyelid lymphatic drainage and this is corroborated by our series. Further data will elucidate the biology of eyelid lymphatic channels in humans but the preauricular basin may be the prime lymphatic metastastic site in eyelid malignancies.

Single application of a CB1 receptor antagonist rapidly following head injury prevents long-term hyperexcitability in a rat model.

Effective prophylaxis for post-traumatic epilepsy currently does not exist, and clinical trials using anticonvulsant drugs have yielded no long-term antiepileptogenic effects. We report that a single, rapid post-traumatic application of the proconvulsant cannabinoid type-1 (CB1) receptor antagonist SR141716A (Rimonabant-Acomplia) abolishes the long-term increase in seizure susceptibility caused by head injury in rats. These results indicate that, paradoxically, a seizure-enhancing drug may disrupt the epileptogenic process if applied within a short therapeutic time window.

Homeostatic plasticity studied using in vivo hippocampal activity-blockade: synaptic scaling, intrinsic plasticity and age-dependence.

Homeostatic plasticity is thought to be important in preventing neuronal circuits from becoming hyper- or hypoactive. However, there is little information concerning homeostatic mechanisms following in vivo manipulations of activity levels. We investigated synaptic scaling and intrinsic plasticity in CA1 pyramidal cells following 2 days of activity-blockade in vivo in adult (postnatal day 30; P30) and juvenile (P15) rats. Chronic activity-blockade in vivo was achieved using the sustained release of the sodium channel blocker tetrodotoxin (TTX) from the plastic polymer Elvax 40W implanted directly above the hippocampus, followed by electrophysiological assessment in slices in vitro. Three sets of results were in general agreement with previous studies on homeostatic responses to in vitro manipulations of activity. First, Schaffer collateral stimulation-evoked field responses were enhanced after 2 days of in vivo TTX application. Second, miniature excitatory postsynaptic current (mEPSC) amplitudes were potentiated. However, the increase in mEPSC amplitudes occurred only in juveniles, and not in adults, indicating age-dependent effects. Third, intrinsic neuronal excitability increased. In contrast, three sets of results sharply differed from previous reports on homeostatic responses to in vitro manipulations of activity. First, miniature inhibitory postsynaptic current (mIPSC) amplitudes were invariably enhanced. Second, multiplicative scaling of mEPSC and mIPSC amplitudes was absent. Third, the frequencies of adult and juvenile mEPSCs and adult mIPSCs were increased, indicating presynaptic alterations. These results provide new insights into in vivo homeostatic plasticity mechanisms with relevance to memory storage, activity-dependent development and neurological diseases.

Prevention of plasticity of endocannabinoid signaling inhibits persistent limbic hyperexcitability caused by developmental seizures.

Depolarization-induced suppression of inhibition (DSI) is an endocannabinoid-mediated short-term plasticity mechanism that couples postsynaptic Ca2+ rises to decreased presynaptic GABA release. Whether the gain of this retrograde synaptic mechanism is subject to long-term modulation by glutamatergic excitatory inputs is not known. Here, we demonstrate that activity-dependent long-term DSI potentiation takes place in hippocampal slices after tetanic stimulation of Schaffer collateral synapses. This activity-dependent, long-term plasticity of endocannabinoid signaling was specific to GABAergic synapses, as it occurred without increases in the depolarization-induced suppression of excitation. Induction of tetanus-induced DSI potentiation in vitro required a complex pathway involving AMPA/kainate and metabotropic glutamate receptor as well as CB1 receptor activation. Because DSI potentiation has been suggested to play a role in persistent limbic hyperexcitability after prolonged seizures in the developing brain, we used these mechanistic insights into activity-dependent DSI potentiation to test whether interference with the induction of DSI potentiation prevents seizure-induced long-term hyperexcitability. The results showed that the in vitro, tetanus-induced DSI potentiation was occluded by previous in vivo fever-induced (febrile) seizures, indicating a common pathway. Accordingly, application of CB1 receptor antagonists during febrile seizures in vivo blocked the seizure-induced persistent DSI potentiation, abolished the seizure-induced upregulation of CB1 receptors, and prevented the emergence of long-term limbic hyperexcitability. These results reveal a new form of activity-dependent, long-term plasticity of endocannabinoid signaling at perisomatic GABAergic synapses, and demonstrate that blocking the induction of this plasticity abolishes the long-term effects of prolonged febrile seizures in the developing brain.

Opposing modifications in intrinsic currents and synaptic inputs in post-traumatic mossy cells: evidence for single-cell homeostasis in a hyperexcitable network.

Recent experimental and modeling results demonstrated that surviving mossy cells in the dentate gyrus play key roles in the generation of network hyperexcitability. Here we examined if mossy cells exhibit long-term plasticity in the posttraumatic, hyperexcitable dentate gyrus. Mossy cells 1 wk after fluid percussion head injury did not show alterations in their current-firing frequency (I-F) and current-membrane voltage (I-V) relationships. In spite of the unchanged I-F and I-V curves, mossy cells showed extensive modifications in Na(+), K(+) and h-currents, indicating the coordinated nature of these opposing modifications. Computational experiments in a realistic large-scale model of the dentate gyrus demonstrated that individually, these perturbations could significantly affect network activity. Synaptic inputs also displayed systematic, opposing modifications. Miniature excitatory postsynaptic current (EPSC) amplitudes were decreased, whereas miniature inhibitory postsynaptic current (IPSC) amplitudes were increased as expected from a homeostatic response to network hyperexcitability. In addition, opposing alterations in miniature and spontaneous synaptic event frequencies and amplitudes were observed for both EPSCs and IPSCs. Despite extensive changes in synaptic inputs, cannabinoid-mediated depolarization-induced suppression of inhibition was not altered in posttraumatic mossy cells. These data demonstrate that many intrinsic and synaptic properties of mossy cells undergo highly specific, long-term alterations after traumatic brain injury. The systematic nature of such extensive and opposing alterations suggests that single-cell properties are significantly influenced by homeostatic mechanisms in hyperexcitable circuits.

Inclusion body myositis-like phenotype induced by transgenic overexpression of beta APP in skeletal muscle.

Inclusion body myositis (IBM), the most common age-related muscle disease in the elderly population, is an incurable disorder leading to severe disability. Sporadic IBM has an unknown etiology, although affected muscle fibers are characterized by many of the pathobiochemical alterations traditionally associated with neurodegenerative brain disorders such as Alzheimer's disease. Accumulation of the amyloid-beta peptide, which is derived from proteolysis of the larger amyloid-beta precursor protein (betaAPP), seems to be an early pathological event in Alzheimer's disease and also in IBM, where in the latter, it predominantly occurs intracellularly within affected myofibers. To elucidate the possible role of betaAPP mismetabolism in the pathogenesis of IBM, transgenic mice were derived in which we selectively targeted betaAPP overexpression to skeletal muscle by using the muscle creatine kinase promoter. Here we report that older (>10 months) transgenic mice exhibit intracellular immunoreactivity to betaAPP and its proteolytic derivatives in skeletal muscle. In this transgenic model, selective overexpression of betaAPP leads to the development of a subset of other histopathological and clinical features characteristic of IBM, including centric nuclei, inflammation, and deficiencies in motor performance. These results are consistent with a pathogenic role for betaAPP mismetabolism in human IBM.