Matthew R. Edmunds

Drug discovery in ophthalmology: past success, present challenges, and future opportunities

BackgroundDrug discovery has undergone major transformations in the last century, progressing from the recognition and refinement of natural products with therapeutic benefit, to the systematic screening of molecular libraries on whole organisms or cell lines and more recently to a more target-based approach driven by greater knowledge of the physiological and pathological pathways involved. Despite this evolution increasing challenges within the drug discovery industry are causing escalating rates of failure of development pipelines.DiscussionWe review the challenges facing the drug discovery industry, and discuss what attempts are being made to increase the productivity of drug development, including a refocusing on the study of the basic biology of the disease, and an embracing of the concept of ‘translational research’. We consider what ophthalmic drug discovery can learn from the sector in general and discuss strategies to overcome the present limitations. This includes advances in the understanding of the pathogenesis of disease; improvements in animal models of human disease; improvements in ophthalmic drug delivery and attempts at patient stratification within clinical trials.SummaryAs we look to the future, we argue that investment in ophthalmic drug development must continue to cover the whole translational spectrum (from ‘bench to bedside and back again’) with recognition that both biological discovery and clinical understanding will drive drug discovery, providing safe and effective therapies for ocular disease.

Defining the Limits of Normal Conjunctival Fornix Anatomy in a Healthy South Asian Population

Purpose Quantifying the extent of conjunctival fibrosis for documentation of progression in conjunctival scarring disease is a clinical challenge. Measurement of forniceal foreshortening facilitates monitoring of these disorders. This study aims (1) to define the limits of the normal human conjunctival fornices and how these alter with age and (2) to provide normative data for upper and lower fornix depths (FDs) and fornix intercanthal distance (FICD) within a healthy South Asian, racially distinct population. Design Epidemiologic, cross-sectional study. Participants A total of 240 subjects with national origins from South Asia, with no known ocular history and normal adnexal and conjunctival examination, aged 20 to 80 years. Methods An FICD modification of a custom-designed fornix depth measurer (FDM) was validated and used for measurement of both lower and upper FDs together with FICDs in 480 healthy eyes with no ocular comorbidities. Data were analyzed using repeated-measures analysis of variance and presented as means with 95% confidence intervals (CIs). Main Outcome Measures Mean lower and upper FDs and FICD for the entire cohort, stratified according to age decade and sex. Results For this South Asian population, the overall upper and lower FDs were 15.3 mm (95% CI, 14.9–15.6) and 10.9 mm (95% CI, 10.7–11.1), respectively, with FICD defined as 32.9 mm (95% CI, 32.5–33.4) (upper) and 31.7 mm (95% CI, 31.3–32.1) (lower). With increasing age, a progressive reduction of all measured parameters (P < 0.001) was noted, with female subjects having significantly shallower fornices (upper FD, P < 0.001; lower FD, P < 0.001; upper FICD, P = 0.081; and lower FICD, P = 0.015). Conclusions This is the first study to define the limits of normal upper FD and FICDs in any population group. Our study demonstrates sex variations and progressive conjunctival shrinkage with age. Although it provides important, objective data for normal forniceal anatomy, further study is recommended in other populations to confirm the generalizability of these data or to enable normal comparative datasets for the assessment of conjunctival scarring disorders among all anthropological groups.

Ophthalmic manifestations of atypical IgD multiple myeloma.

A previously healthy 32-year-old Caucasian female presented with sudden-onset horizontal diplopia following a paroxysm of coughing. She had recently sustained a pubic ramus fracture during an innocuous fall and had also noted a firm lump developing at the right side of her forehead. On examination, she had a right fronto-temporal mass. Visual acuities were 6/6 bilaterally. There was reduced abduction of the right eye, bilateral white, granular corneal opacities and evidence of bilateral optic disc swelling. Haematological investigations revealed normocytic anaemia, hypercalcaemia and raised erythrocyte sedimentation rate (ESR). CT showed lytic foci throughout the skull, ribs, scapulae, spine, pelvis and upper femora. Serum protein electrophoresis revealed immunoglobulin D (IgD)-kappa paraproteinaemia; urine electrophoresis showed free light chain kappa and bone marrow biopsy demonstrated 87% plasma cells. A diagnosis of IgD multiple myeloma was made, with subsequent chemotherapeutic treatment and eventual autologous stem cell transplant resulting in resolution of neuro-ophthalmic manifestations and prolonged disease remission.

High Rate of Incomplete Resection After Primary Excision of Eyelid BCC: Multi-Staged Resection Rarely Needs More Than Two Procedures

Purpose: Small, well-demarcated, biopsy-proven periocular basal cell carcinomas (BCC) are often excised in a single stage with immediate reconstruction when histology or location is considered low-risk. We investigated margin clearance in patients undergoing primary excision and immediate reconstruction (PER) versus multi-staged fast paraffin excision (MSE) and reviewed risk factors for incomplete excision. Methods: Retrospective, interventional, comparative case series of periocular BCCs excised over a 3-year period (2006–2008). Results: Ninety consecutive patients with periocular BCC (average age 77 ± 10.1 years, 60% females) were included. 39% (35/90) underwent PER with the remainder managed by MSE (55/90, 61%). Patients undergoing MSE had larger lesions (38% >10 mm versus 23% PER) which were more likely to involve the medial canthus (25 versus 11% PER). Incomplete histological clearance was noted in 34% (12/35) patients after PER. Only 3/55 (5%) needed third stage of excision in the MSE group with final incomplete excision in two cases (3.6%) that did not undergo a third stage excision. No significant risk factors were found likely to predict residual BCC overall, after first excision stage. Subgroup analysis for patients undergoing PER showed multiple lesions as the only statistically significant factor for incomplete excision. Conclusion: This study shows an unacceptably high rate of incomplete resection with primary excision and repair using a standard 3 mm margin. The majority of lesions undergoing multi-stage excision required no more than two stages for complete removal. Multi-stage excision with histological confirmation of clear margins prior to reconstruction is recommended for routine management of all periocular BCC.

Few university students from overseas have been vaccinated against meningococcal infection

EDITOR—It is now a year since the new conjugated meningococcal group C vaccine was introduced to the United Kingdom.1 Students in higher education are at a higher risk of meningococcal disease than other students and were targeted in the government vaccination campaign. Because of the limited supply and late licensing of the new vaccine the pre-existing polysaccharide vaccine was used. To determine the effect of the policy we performed a cross sectional study of 3028 first year undergraduate and overseas postgraduate students …

Autoimmune encephalopathy in the context of Graves' disease with ophthalmopathy

Dear Editor, More than 40 years after its initial description by Brain et al., ‘Hashimoto’s encephalopathy’ (HE) remains an enigmatic clinical entity. Although no universally accepted definition exists, commonly employed diagnostic criteria include an acute or subacute presentation with neuropsychiatric symptoms consistent with encephalopathy, presence of serum antithyroid antibodies and exclusion of alternative infective or metabolic causes.The vast majority of HE cases described in the literature relate to patients demonstrating either hypothyroidism or euthyroidism. Here, we describe an atypical presentation of autoimmune encephalopathy in the context of autoimmune hyperthyroidism (Graves’ disease). A 67-year-old female patient had a 3-year history of Graves’ hyperthyroidism, well controlled on long-term carbimazole. She had a 5-year history of moderate Graves’ ophthalmopathy, only requiring squint surgery. Her past medical history included coeliac disease and hypertension; she smoked but did not drink alcohol regularly. Other medications included aspirin, sertraline and bendroflumethiazide. On clinic review, she appeared confused, unkempt and had evidently lost weight. Her family reported a subacute history of cognitive decline over the preceding month (including disorientation, falls and inability to perform daily routine tasks such as doing the laundry or using her mobile phone), with dramatic deterioration during the preceding 5 days. They also reported an acute hospital admission with confusion, which resolved spontaneously within 24 h, 4 weeks earlier. On examination, she demonstrated a coarse tremor of her upper and lower limbs but was clinically and biochemically euthyroid. She had normal vital signs and was afebrile. Neurological assessment revealed tremor and ankle clonus, with bilateral hyperreflexia, but normal plantar responses. Full blood count, basic biochemistry and septic screen (blood cultures, chest X-ray, urine microscopy and cultures) were normal. Her thyroid function tests were consistent with good control with carbimazole, with a FT4 of 19 3 pM, (normal range 10–22 pM) and a TSH of 0 14 miu/l (normal range 0 3–4 5 miu/l). A CT scan of her brain showed no abnormalities. She was commenced on empirical treatment for viral encephalitis with intravenous aciclovir. The only cerebrospinal fluid (CSF) abnormality detected was high protein (0 94 g/dl), with negative oligoclonal bands and CSF microbiology, including negative viral PCR (herpes simplex types 1 and 2, varicella zoster, cytomegalovirus, Epstein–Barr virus, adenovirus, enterovirus, polyoma virus). She manifested a fluctuating mental state for the next 3 days, with frequent episodes of agitation. On the fourth day of her admission, she suffered three brief tonic–clonic seizures. Anti-epileptic drug treatment was commenced. Neurology review raised the possibility of autoimmune encephalopathy, and high-dose intravenous dexamethasone (4 mg three times per day) was introduced. An autoimmune screen revealed high antithyroid peroxidase (1009 U/ml) and antinuclear antibody (1:1600) titres; at this point, a modest elevation of her inflammatory markers was noted (Neutrophils 9 1/ll, CRP 53 mg/l). Her electroencephalogram (EEG) revealed diffuse slow-wave activity, while an MRI of the brain with contrast was unremarkable. HIV and syphilis serology, anti-N-methyl D-aspartate (NMDA) receptor antibodies, voltage-gated potassium channel antibodies, GAD antibodies and paraneoplastic antibody screen were all negative. A putative diagnosis of autoimmune encephalitis (likely ‘Hashimoto’s encephalitis’) was made. She responded well to immunosuppression with glucocorticoids, with the tremor and hyper-reflexia disappearing and her cognitive state returning to near normal within 6 days. Intravenous ceftriaxone and aciclovir were stopped after 7 days once the viral PCR was known to be negative. A repeat lumbar puncture, 10 days after the first, revealed a normal protein content (0 52 g/l), and she was discharged on prednisolone 40 mg daily (tapering regimen). On follow-up a month later, she showed complete neurocognitive recovery, corroborated by a normal EEG, and reported no further convulsive episodes. There are more than 100 published cases of HE; however, to our knowledge, only nine occurred in the context of clinical hyperthyroidism. The neuropsychiatric manifestations of HE are remarkably diverse, and may include cognitive and behavioural changes ranging from confusion to overt psychosis, seizures, extrapyramidal symptoms (tremor, chorea, myoclonus) and cerebellar symptoms (ataxia, central nystagmus). Some cases are characterized by vascular symptoms emulating stroke. In the absence of a definitive diagnostic test, HE remains a diagnosis of exclusion which requires comprehensive investigation to exclude important differential diagnoses. This should include thyroid function tests to exclude poorly controlled hyperthyroidism or profound hypothyroidism, serum electrolytes, renal and liver function tests, blood gases and toxicology to exclude metabolic or toxic causes, septic screen, CT head and MRI head to exclude structural intracranial pathology (including ischaemic and inflammatory lesions) and a lumbar puncture to exclude central nervous system infection. EEG is used to exclude nonconvulsive status epilepticus and may show changes of encephalopathy. The mainstay of treatment is immunosuppression. The vast majority of reported cases of HE responded well to glucocorticoids (although there may be selection bias, as many authors would only endorse the diagnosis of HE on condition of a successful clinical outcome with immunosuppression). Chong et al., in their review of 85 published cases of HE, reported a 96% response rate to glucocorticoids. Many experts consider the term ‘Hashimoto’s encephalopathy’ a misnomer, as there is no evidence that the antithyroid

Orbital infarction with haematoma in sickle cell disease

A 5 year old boy with sickle cell disease presented with a two day history of painful right periocular swelling. Initial treatment was with intravenous antibiotics for suspected orbital …

Intraocular surgery with warfarin anticoagulation

Intraocular surgery with warfarin anticoagulation Batra et al. highlight discrepancies in perioperative management of warfarin anticoagulation with cataract surgery but do not address reasons for the apparent poor compliance with national guidelines. The guidelines recommend operating within the therapeutic range and are based principally on a review of different anesthesia techniques. However, the increase in complications with a sharp needle or a sub-Tenon cannula in patients taking warfarin (6.2% versus 4.3%) has been largely related to subconjunctival hemorrhage rather than sight-threatening hemorrhagic complications. Clinical decisions are individualized and based on a range of considerations. A scenario of excessive anticoagulation can be disconcerting for most cataract surgeons performing elective procedures with typically excellent visual outcomes. Respondents (84.7%) stated the international normalized ratio (INR) level influenced their decision to proceed with surgery, with most considering a threshold of 3 acceptable. It might be reasonable to accept that risk of sight-threatening complications influenced the decision of these respondents, who record the INR level and are aware of the transient hypercoagulable state induced by a blanket cessation of warfarin. Furthermore, 13 suprachoroidal hemorrhages were reported with warfarin. Details of not just INR levels, but also medical/ocular risk factors may clarify the cause. Most reports group warfarinized patients together without accounting for differing anticoagulation levels. Higher postoperative hemorrhage in patients having vitreoretinal procedures with INR therapeutic levels of 2.5 or higher versus subtherapeutic levels of 1.5 or lower (16.7% versus 7.7%) has been reported. Recommending a dose modification for apprehensive surgeons does not address the main issue of whether the surgeon should be apprehensive. We would be more concerned with surgeons whose decision to operate was not influenced by any INR level. Might it not be prudent to review factors such as unstable INR levels, uncontrolled hypertension, and generally high-risk eyes with ischemic pathology/glaucoma than simply follow guidelines? No mention is made of clopidogrel having an even

Patients’ expectations for the functional and psychosocial outcomes of orbital decompression surgery for thyroid eye disease: a qualitative study

Abstract Patients with appearance-altering conditions may be dissatisfied with the outcomes of reconstructive surgery due to unmet expectations. This study explored patients’ expectations of orbital decompression surgery for thyroid eye disease (TED) and whether these were met. Semi-structured interviews were conducted at two times: (1) in the weeks after patients were listed for decompression surgery and before surgery; (2) up to 12 months after surgery. Thematic analysis was performed for each time point, to identify themes within the data. Fourteen adults with TED were interviewed prior to surgery and five were followed up after surgery. Thematic analyses found: (1) Prior to surgery, patients had formed expectations through online information about the procedure, consultations with physicians, the impact TED had on their lives, and speaking to relevant others. Patients had specific expectations about the procedure, the recovery, post-operative appearance and post-operative vision. (2) After surgery, patients generally felt their appearance and well-being had improved. However, dissatisfaction was linked to unanticipated specific aspects of surgical care, recovery, or appearance. Dissatisfaction can arise from unmet expectations for the outcomes of reconstructive surgery. Physicians should be aware of the processes by which patients form expectations, for example different types and quality of online information. Ensuring that preoperative expectations are realistic could enhance satisfaction after surgery.