The Unmet Challenge of Diagnosing and Treating Photophobia.

BACKGROUND: Although patients with abnormal light sensitivity may present to an ophthalmologist or optometrist for the evaluation of photophobia, there are no previous reviews of the most common causes of this symptom. METHODS: We conducted a retrospective chart review of patients who presented to our eye center between 2001 and 2009 primarily for the evaluation of photophobia. We recorded demographics, ocular examination findings, and diagnoses of these patients. RESULTS: Our population included 58 women and 53 men. The mean age at presentation to the clinic was 37 years (range 6 months-94 years). The most frequent cause of photophobia was migraine headache (53.7%), followed by dry eye syndrome (36.1), ocular trauma (8.2%), progressive supranuclear palsy (6.8%), and traumatic brain injury (4.1%). A significant proportion of patients (25.9%) left the clinic without a cause for their photophobia documented by the examining physician (11.7% of adults and 69.4% of children). CONCLUSIONS: Photophobia affects patients of all ages, and many patients are left without a specific diagnosis, indicating a significant knowledge gap among ophthalmologists and optometrists evaluating these patients.

New and future migraine therapy.

Modern neuroscience advanced our understanding of putative migraine mechanisms, which led to improved therapeutics. Indeed, mechanism-based acute migraine therapy gained steam in the early 1990s after the introduction of the triptans (5-HT1B,D agonists). Post-triptans, novel targets such as calcitonin gene-related peptide (CGRP) antagonists, inhibitors of excitatory glutamatergic receptors, and nitric oxide synthase (NOS) inhibitors are leading the pack in this exploding field of discovery research. In contrast, novel therapeutic targets for migraine prevention are lacking despite a hugely unmet need. To date, migraine prophylactic drugs are advanced based on expanded indications for already approved pharmaceuticals (e.g., topiramate, valproate, propranolol, and timolol). An improved understanding of the predisposition to an attack, genomic discoveries, valid and reliable biomarkers and surrogates, and predictive preclinical models likely will unravel the neuronal substrates for central hyperexcitability and nociceptive dysmodulation, hopefully leading us to better mechanism-based targets for prevention, and ultimately yielding drugs with optimal therapeutic ratios or indices.

Prophylactic pharmacotherapy for migraine headaches.

Migraine therapeutics are pharmacological, including acute and preventive, nonpharmacological and/or both. Preventive pharmacological strategies serendipitously were discovered to be effective and include drugs from various pharmacological classes (e.g., beta-adrenergic blocker, anticonvulsant, tricyclic antidepressants, serotonin receptor antagonist). Converging level I evidence and clinical experience support the use of the antidepressant amitriptyline, the anticonvulsants divalproex and topiramate, and the beta-adrenergic blockers propranolol, timolol, and metoprolol in migraine prevention. Other options for migraine prophylaxis exist, but the level of evidence in support of their use is not as robust. All of these drugs have varying degrees of adverse effects, some of which can limit their use. Balancing potential efficacy with risk of adverse effects, addressing patients' expectations and desires, complying with management recommendations, adequate follow up, and accurate assessment of treatment goals are key to migraine prevention. Finally, future migraine-preventive drugs likely will target migraine mechanisms more specifically, which undoubtedly will enhance the therapeutic index.

Partial dopamine loss enhances activated caspase-3 activity: differential outcomes in striatal projection systems.

Parkinson's disease (PD) is a basal ganglia disorder. Motor symptoms develop insidiously following substantial neurodegeneration of the dopamine (DA) neurons in the nigrostriatal system and produce slowed, infrequent movements, postural instability, and gait changes. A thorough understanding of neurochemical compensations occurring in the striatum during early stages of PD is crucial in identifying components that are altered initially as the DA is depleted. Producing an incomplete lesion of the nigrostriatal DA system in rats would mimic the principal early neurochemical features of human PD. We infused 6-hydroxydopamine unilaterally into the substantia nigra to reach a target of approximately 50% depletion in striatal DA at 4 weeks. This was evaluated by HPLC analysis of tissue DA content and monitored behaviorally by forepaw use reflecting asymmetries in striatal DA levels. DA loss was assessed by using tyrosine hydroxylase immunohistochemical staining, and the data were conjoined with the behavioral assessments. We found that activated caspase-3, its actin cleavage product fractin, and components of the apoptosome were increased significantly in DA-depleted striatum. Thus mobilization of the intrinsic programmed cell death pathway occurred, without cell loss. Elevations in apoptogenic proteins were pronounced in enkephalinergic striatopallidal neurons compared with the substance P-containing striatonigral neurons. Our findings suggest that cellular homeostatic imbalances that accompany even mild striatal DA depletion take time to develop, differentially affect the striatal output pathways, and may be an important feature of early-stage PD. These observations could be capitalized upon to develop therapeutic interventions in the preclinical phases of the disorder.

Future pharmacologic targets for acute and preventive treatments of migraine.

Advances in investigative research (e.g., functional magnetic resonance imaging) have made it possible to study putative migraine processes and better understand the pathophysiology of the disorder. Consequently, the apparent opposing vascular and neuronal theories of migraine are now reconciled into a neurovascular hypothesis that pieces together migrainous events and allows us to better target such events in the hope of providing safe and effective therapies. Parallel discoveries in the fields of pharmacology, physiology, genetics and other biomedical disciplines will lead to the development of optimal migraine therapeutics. Such discoveries have already yielded some major enhancement in acute migraine treatment with the development of sumatriptan (Imitrex, GlaxoSmithKline) and other triptans and the trajectory is likely to be exponential. Novel targets, such as calcitonin gene-related peptide antagonists and inhibitors of excitatory glutamatergic receptors, are leading the pack but many other promising targets are in development. The post-sumatriptan decades will witness treatment strategies that will improve the therapeutic index of acute therapies and others which will effectively and safely prevent migraine attacks.

Generation and characterization of monoclonal antibodies to the phenolic glycolipid of Mycobacterium leprae

Nine cloned cell lines producing antibodies to the unique phenolic glycolipid of Mycobacterium leprae have been established as a result of fusions with spleens from mice immunized with the glycolipid complexed with methylated bovine serum albumin. One of the antibodies was relatively nonspecific, binding to a related glycolipid from Mycobacterium kansasii, but the remaining antibodies were specific for the M. leprae lipid. Some of the antibodies required the intact (trisaccharide) carbohydrate portion for recognition of the glycolipid antigen, whereas others recognized partially hydrolyzed forms lacking one or two sugar residues. Monoclonal antibodies directed at the terminal saccharide of the glycolipid showed the greatest specificity for M. leprae in enzyme-linked immunoassays. These antibodies brightly labeled whole mycobacteria in indirect immunofluorescence experiments, demonstrating the surface location of M. leprae-specific determinants of the glycolipid antigen. In addition to their use in providing information about the antigenic properties of the phenolic glycolipid, these antibodies have potential applications for elucidating the roles of glycolipid in the pathogenesis of leprosy.