Five decades of the use of botulinum toxin in ophthalmology.

Botulinum toxin (BoNT) has been known for over 50 years. It has conquered many areas of medicine and has become indispensable in contemporary medicine. Now, BoNT is used to treat at least 26 conditions in six medical specialties. Although the use of BoNT began in strabology, it became the gold standard for many ophthalmologic pathologies. The present review of the literature focuses on the use of BoNT in ophthalmology and treatment of the following conditions: blepharospasm, facial hemispasm, facial palsy, spastic entropion, strabismus, endocrine orbitopathy, convergence spasm, and facial trauma. We conclude that nearly half a century of experience in utilizing BoNT in ophthalmology ensured a satisfactory level of effectiveness and safety for patients with many pathologies. Areas of future research include the application of BoNT in new selected indications, the development of the route of application without injections, and the development of long-acting BoNT forms for patients who require repeated long-term treatment.

Orbital inflammation and colitis in pediatric IgG4-related disease: A case report and review of the literature.

IgG4-related disease (IgG4-RD) is an inflammatory disorder characterized by tumor-like swelling in one or more organs, elevated serum IgG4 levels, and histological alterations with infiltration of IgG4-positive plasma cells. IgG4-RD is rare and likely underdiagnosed in children. We report a case of a 16-year-old girl with IgG4-positive colitis that developed weeks after IgG4-related ophthalmic disease and discuss diagnosis and treatment in the context of the literature available. Since the pathophysiology of IgG4-RD is unknown, treatment options are empiric and, for the most part, untargeted. Systemic corticosteroid treatment is the basis of anti-inflammatory treatment in IgG4-RD and induced early remission in our patient. During corticosteroid taper, the patient developed weight loss and intestinal inflammation. Histopathological assessment of the intestinal walls confirmed IgG4-positive colitis. Immune-modulating treatment with non-biologic (e.g., methotrexate (MTX) and mycophenolate mofetil) or biologic (rituximab) disease-modifying antirheumatic drugs has been reported in treatment refractory or corticosteroid-dependent patients. The patient responded to treatment with anti-inflammatory therapy with food rich in TGF-ß2 (modulen) and MTX. This is one of the first pediatric patients reported with IgG4-related colitis extending the phenotype of pediatric IgG4-RD. International collaboration to prospectively document clinical presentation and treatment responses may help to further establish the phenotype and treatment options and to raise awareness for IgG4-RD.

High-dose intravenous methylprednisolone in juvenile non-infectious uveitis: A retrospective analysis.

Non-infectious uveitis is associated with visual impairment and blindness. Non-biologic treatment for non-infectious uveitis is not based on strong evidence. A retrospective chart review was conducted to investigate treatment response to high-dose intravenous methylprednisolone (IVMP) in children with non-infectious uveitis. Fifty-six patients (93 eyes affected) were included. In 29% uveitis was associated with juvenile idiopathic arthritis. Uveitis predominately affected the anterior segment, was bilateral and recurrent. Complications were common and included visual loss, synechiae, cataract and/or retinal lesions. Patients received up to 5 IVMP at monthly intervals. Visual acuity improved at 3 and 6 months. Anterior chamber cells, synechiae, keratic precipitates, papillary and/or macular edema improved at 3 months. Children treated with ≥3 IVMP (vs 1 IVMP) experienced trends towards fewer relapses, fewer cataracts and less frequently required treatment with biologic agents. High-dose IVMP induce rapid improvement in children with non-infectious uveitis. Prospective randomized trials are required to confirm results.

Cytokine production in thyroid eye disease: in vitro effects of dexamethasone and IL-6 blockade with tocilizumab.

PURPOSE: To compare IL-6, sIL-6R, and IL-17 secretion in peripheral blood mononuclear cells (PBMCs) cultured with tocilizumab (a humanized monoclonal antibody against the interleukin-6 receptor), dexamethasone, and placebo, obtained from patients with thyroid eye disease (TED) and healthy controls. METHODS: The study was a prospective proof of concept test. We cultured peripheral blood mononuclear cells from TED patients and healthy controls with tocilizumab, dexamethasone, and placebo. IL-6, sIL-6R, and IL-17 levels in supernatants obtained from PBMCs cultures were analyzed by ELISA. RESULTS: We included seventeen patients with thyroid eye disease (12 females and five males). The mean age was 49 years. Both dexamethasone and tocilizumab influenced IL-6 and IL-6Rs levels in patients' group. Supernatants obtained from PBMCs treated with dexamethasone showed 77.2% and 82.8% lower IL-6 levels compared with those cultured with placebo and tocilizumab, respectively. Furthermore, overnight culture of PBMCs with dexamethasone showed significantly lower sIL-6R secretion compared with untreated (33.71%, p = 0.04) and tocilizumab treated (58.21%, p = 0.01) PBMCs. Neither dexamethasone nor tocilizumab affected IL-17 concentrations in PBMCs cultures. CONCLUSIONS: Both dexamethasone and tocilizumab affect the IL-6/sIL-6R system. Specifically, dexamethasone reduces and tocilizumab increases the levels of these cytokines in PBMCs cultures. These results strengthen the molecular rationale for interrogating the efficacy of tocilizumab in steroid-resistant TED, as IL-6 seems to be a common target for both anti-IL-6R antibody and steroids.

The short-term effect of acupuncture on different ocular blood flow parameters in patients with primary open-angle glaucoma: a randomized, clinical study.

INTRODUCTION: To investigate the effect of acupuncture on different ocular blood flow (OBF) parameters in patients with primary open-angle glaucoma (POAG). PATIENTS AND METHODS: In a prospective, randomized study, 56 POAG patients were randomly assigned either to an eye-specific acupuncture (group I, n=28) or to an eye-unspecific acupuncture treatment (group II, n=28). Blood flow parameters were measured before and 10 minutes after treatment. Parapapillary retinal blood flow was determined by the Heidelberg retina flowmeter. Retinal vessel diameters were measured by the dynamic vessel analyzer. Pulsatile ocular blood flow, ocular pulse amplitude, and IOP were investigated by the Langham OBF system. Systemic blood pressure was obtained additionally. RESULTS: Pulsatile ocular blood flow increased significantly after the eye-specific acupuncture treatment from 5.6±4.3 to 6.7±4.9 µL/min (P=0.014). There was no significant change in parapapillary retinal blood flow, retinal vessel diameter, systemic blood pressure, or IOP after treatment in neither of the two groups. CONCLUSION: An eye-specific acupuncture treatment may affect OBF in POAG patients.

Measurement of Orbital Biomechanical Properties in Patients with Thyroid Orbitopathy Using the Dynamic Scheimpflug Analyzer (Corvis ST).

PURPOSE: To investigate orbital biomechanical properties in patients with thyroid orbitopathy and in age- and gender-matched healthy subjects using the Corvis-ST (CST, Oculus Wetzlar, Germany). METHODS: The CST allows a non-contact tonometry with an ultra-high-speed Scheimpflug device to record the deformation of the cornea during an air pulse. Biomechanical response parameters (intraocular pressure (IOP), whole eye movement length (WEMl) and time (WEMt), deflection amplitude 2 mm ratio max, deflection amplitude max, stiffness parameter, and biomechanically corrected IOP were measured in 39 patients with thyroid orbitopathy (= group I) and in 33 age- and gender-matched healthy subjects (= group II) using the CST. RESULTS: Mean age in group I was 54.3 ± 11.6 years and in group II 54.2 ± 12.3 years with no statistical significant difference between the groups (P = 0.98). The gender distribution between the groups was not statistically significantly different (P = 0.51). Mean central corneal thickness was 571 ± 30 µm in group I and 563 ± 36 µm in group II (P = 0.306). There were statistically significant differences (P < 0.001) between groups I and II in mean IOP (19.3 ± 4.5 vs. 14.8 ± 2.3 mmHg, mean biomechanically corrected IOP (17.1 ± 3.4 vs. 13.4 ± 2.1 mmHg), mean WEMl (207 ± 57 vs. 322 ± 50 µm), mean WEMt (20.5 ± 1.0 vs. 21.9 ± 0.7 ms), mean IOP-adjusted WEMl (213 ± 56 vs. 314 ± 62 µm), and in mean stiffness parameter (132.5 ± 29.6 vs. 107.8 ± 23.3 mmHg/mm), respectively. CONCLUSION: Biomechanical parameters as measured by the CST were significantly reduced in patients with thyroid orbitopathy compared to age- and gender-matched healthy subjects, indicating a reduction in orbital compliance in thyroid orbitopathy. The parameters WEMl and WEMt might be a useful diagnostic tool to evaluate the condition of the eyeball within the orbit.

Thoracic Hemisection in Rats Results in Initial Recovery Followed by a Late Decrement in Locomotor Movements, with Changes in Coordination Correlated with Serotonergic Innervation of the Ventral Horn.

Lateral thoracic hemisection of the rodent spinal cord is a popular model of spinal cord injury, in which the effects of various treatments, designed to encourage locomotor recovery, are tested. Nevertheless, there are still inconsistencies in the literature concerning the details of spontaneous locomotor recovery after such lesions, and there is a lack of data concerning the quality of locomotion over a long time span after the lesion. In this study, we aimed to address some of these issues. In our experiments, locomotor recovery was assessed using EMG and CatWalk recordings and analysis. Our results showed that after hemisection there was paralysis in both hindlimbs, followed by a substantial recovery of locomotor movements, but even at the peak of recovery, which occurred about 4 weeks after the lesion, some deficits of locomotion remained present. The parameters that were abnormal included abduction, interlimb coordination and speed of locomotion. Locomotor performance was stable for several weeks, but about 3-4 months after hemisection secondary locomotor impairment was observed with changes in parameters, such as speed of locomotion, interlimb coordination, base of hindlimb support, hindlimb abduction and relative foot print distance. Histological analysis of serotonergic innervation at the lumbar ventral horn below hemisection revealed a limited restoration of serotonergic fibers on the ipsilateral side of the spinal cord, while on the contralateral side of the spinal cord it returned to normal. In addition, the length of these fibers on both sides of the spinal cord correlated with inter- and intralimb coordination. In contrast to data reported in the literature, our results show there is not full locomotor recovery after spinal cord hemisection. Secondary deterioration of certain locomotor functions occurs with time in hemisected rats, and locomotor recovery appears partly associated with reinnervation of spinal circuitry by serotonergic fibers.

Facial emotion perception and schizophrenia symptoms.

AIM: Emotion recognition is an important aspect of social interactions. Patients suffering from schizophrenia exhibit some disturbances in affective processing. The aim of the study was the evaluation of facial emotion perception and its relation to the psychotic symptoms in schizophrenia patients. METHODS: 102 patients with schizophrenia (F20.0, ICD 10) and 50 healthy volunteers participated in the study; all the subjects were 18-60 years old. Psychical condition was assessed with following diagnostic tools: CGI (Clinical Global Impression Scale), PANSS (Positive and Negative Syndromes Scale), CDSS (Calgary Depression Scale for Schizophrenia), UKU (Side Effect Rating Scale). Facial emotion recognition ability was assessed by SIE-T (Emotional Intelligence Scale - Faces). RESULTS: On the basis of gathered data it was found that patients suffering from schizophrenia performed worse on facial emotion recognition task compared to the healthy subjects. Severity of negative symptoms corresponded with the facial emotion perception impairment. There was no relation found between age of schizophrenia-onset and level of the facial emotion perception impairment, but the facial emotion recognition ability was worsening with the age of the subjects, both healthy and suffering from schizophrenia. CONCLUSIONS: Severity of schizophrenia corresponded with the facial emotion perception impairment.

Bilateral self-inflicted infectious dacryoadenitis.

The aim of this report is to present a case of a patient with bilateral lacrimal gland abscesses in the course of dacryoadenitis. A 45-year-old female patient with a long history of cocaine abuse presented with bilateral bacterial dacryoadenitis and upper lid inflammation with purulent discharge from a palpebral wound of the right upper lid. The diagnosis was confirmed with microbiology culture and an orbital CT scan, which revealed lacrimal gland abscesses. The patient admitted to vigorous eye scratching, which we believe was the mechanism responsible for the process. The infection resolved on targeted antibiotic therapy. This is the first reported case of bilateral infectious dacryoadenitis produced in a self-inflicted mechanism in a cocaine addict.

Grafting of fetal brainstem 5-HT neurons into the sublesional spinal cord of paraplegic rats restores coordinated hindlimb locomotion.

In rodent models of spinal cord injury, there is increasing evidence that activation of the locomotor central pattern generator (CPG) below the site of injury with 5-hydroxytryptamine (5-HT) agonists improves locomotor recovery and restores coordination. A promising means of replacing 5-HT control of locomotion is to graft brainstem 5-HT neurons into the spinal cord below the level of the spinal cord injury. However, it is not known whether this approach improves limb coordination because recovery of coordinated stepping has not been documented in detail in previous studies employing this transplantation strategy. Here, adult rats with complete spinal cord transections at the T9/10 level were grafted with E14 fetal neurons from the medulla at the T10/11 vertebra level one month after injury. The B1, B2 and B3 fetal anlagen of brainstem 5-HT neurons, a grouping that included the presumed precursors of recently described 5-HT locomotor command neurons, were used in these grafts. EMG and video recordings of treadmill locomotion evoked by tail stimulation showed full recovery of inter- and intralimb coordination in the grafted rats. We showed, using systemically applied antagonists, that 5-HT2 and 5-HT7 receptors mediate the improved locomotion after grafting, but through actions on different populations of spinal locomotor neurons. Specifically, 5-HT2 receptors control CPG activation as well as motoneuron output, while 5-HT7 receptors contribute primarily to activity of the locomotor CPG. These results are consistent with the roles for these receptors during locomotion in intact rodents and in rodent brainstem-spinal cord in vitro preparations.

Small cerebral vessel disease in familial amyloid and non-amyloid angiopathies: FAD-PS-1 (P117L) mutation and CADASIL. Immunohistochemical and ultrastructural studies.

Three patients (of two unrelated Polish families) with early-adult onset dementia were subjects of the study. Two cases, previously diagnosed as familial Alzheimer's disease (FAD) with cerebral amyloid angiopathy (CAA), were confirmed by genetic and neuropathological studies, and one case of CADASIL was ultrastructurally confirmed by the presence of vascular granular osmiophilic material. Now the brain autopsy material has been reinvestigated using immunohistochemical (IHC) markers for vascular smooth muscle cells, paying special attention to collagen markers for extracellular matrix components and ultrastructural microvascular changes. In both diseases, IHC examination showed a reduction or loss of expression of smooth muscle actin (SMA) in tunica media of the cerebral arterioles. Fibrous thickening of the wall of the small meningeal arteries, intracerebral arterioles and numerous capillaries, with amyloid or granular deposits, drew our attention. In these vessels, marked expression of fibrillar collagen type III as well as strong immunoreactivity of the basement membrane (BM) component collagen type IV were found. The most damage was observed in the FAD/CAA double-barrel vessel wall and in some CADASIL arterioles changed by fibrinoid necrosis. The fibrous changes of the small vessels were more distinct in CADASIL t han in FAD/CAA. In FAD,electronmicroscopic examination revealed both amyloid and collagen fibres within the thickened BM of capillaries and the small arterioles. Clusters of collagen fibres between lamellae of BM, frequently in a pericyte position,were observed,and some were seen in the degenerated pericytes as well. Typical changes of the pericytes were accumulation of lipofuscin-like material and their degeneration. The mitochondria of the pericytes and of the endothelium were rare and swollen, with damaged and reduced cristae. The VSMCs of the arteriolar walls exhibited degenerative changes with atrophy of the cellular organelles. The fibrous,collagen-richCADASILsmallcerebralvessels,despite the weakness of the vessel wall due to reduction of VSMCs, appeared to be stronger than in FAD/CAA. These findings may suggest an accelerated process of transformation of the small cerebral vessels in which early onset of VSMCs loss is a predominant feature of the vascular changes in both presented diseases.

Ultrastructural picture of blood vessels in muscle and skin biopsy in CADASIL.

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy) is an inherited systemic vascular disorder affecting mainly the central nervous system. We performed detailed ultrastructural examination of the small vessels in the skin and skeletal muscle of a 51-year-old patient with bilateral cerebral white matter lesions, who had a history of two ischaemic strokes. The arterioles were characterized by degeneration and loss of vascular smooth muscle cells (VSMCs). GOM deposits, varied in size and shape, were located in the neighbourhood of the smooth muscle cells, often within an infolding of the cell membrane. No apparent correlations between presence, size or number of GOM deposits and damage severity of vascular smooth muscle cells were seen. Moreover, in some capillaries there were GOM deposits which were seen in the basement membrane near pericytes and endothelial cells. On the other hand, lesions of VMSCs and/or endothelial cells were also visible on the sections of blood vessels devoid of GOM deposits. Genetic tests detected a mutation in exon 4 of the Notch3 gene. It confirmed the initial diagnosis which had been suggested on the basis of the clinical and MRI findings.

Sneddon's syndrome as a disorder of small arteries with endothelial cells proliferation: ultrastructural and neuroimaging study.

We report a 18-year-old female patient with livedo reticularis and neurological disturbances. CT scan showed two big ischemic focuses in the pons, moreover MRI revealed small disseminated ischemic focuses in the pons and deep structures of both brain hemispheres. MRA demonstrated no changes in the big extracranial and intracranial arteries. Since the clinical data and neuroimaging results suggested Sneddon's syndrome, the skin and skeletal muscle biopsy was taken to examine. The immunohistochemical and ultrastructural investigations of the skin biopsy revealed a significant reduction of the lumen of the capillaries and small to medium-sized arteries. Cells surrounding the vascular lumen, frequently with multilayer arrangement and their nuclei placed perpendicularly to the lumen, were CD31, CD34, and sporadically SMA positive. At the ultrastructural level, these proliferating cells showed typical features of endothelial cells: abundant intermediate filaments and Weibel-Palade bodies. Between the endothelial cells some junctions were detached as well in the capillaries as in the small arteries. The smooth muscle cells of the small arteries were electron denser than usual and their cytoplasmic protrusions penetrated to the endothelial cells. The ultrastructural picture of some vessels with a considerably narrow lumen was typical of vessels newly formed during angiogenesis. Neuroimaging including TC, MRI, MRA besides histological, immunohistochemical and ultrastructural evaluation may be useful for diagnosis of Sneddon's syndrome.

Flavonoids and phenol carboxylic acids in the oriental medicinal plant Astragalus membranaceus acclimated in Poland.

Astragalus membranaceus (Fisch.) Bunge has been was successfully acclimated in Central Europe. We report the content of isoflavones and some other polyphenolic compounds in roots and aerial parts that have been analyzed by means of TLC and HPLC. The total amount of isoflavones in leaves, was 0.55 mg g(-1) dry weight, and of the flavonols--up to 3.54 mg g(-1). In the roots isoflavonoid content was extremely variable, but reached 3.04 mg g(-1), whereas flavonols content was 0.49 mg g(-1).

Association analysis of the insertion/deletion polymorphism in serotonin transporter gene in patients with affective disorder.

A polymorphism of serotonin transporter was studied in 226 patients with affective disorders (n = 132 for bipolar, n = 94 for unipolar affective disorder) and in 213 healthy subjects. Consensus diagnosis by at least two psychiatrists, according to the ICD-10 and DSM-IV criteria was made for each patient using SCID (Structured Clinical Interview for DSM-IV Axis I Disorders). A functional polymorphism in the promoter region of serotonin transporter gene, where 44 bp are either inserted (long allele) or deleted (short allele) was analysed. Genotype s/s was significantly more frequent in patients comparing to the control group (P = 0.011 for bipolar and P = 0.003 for unipolar affective disorder)--the most marked association was found in males with bipolar and unipolar illness. The allele frequencies also differ significantly between patients and controls (P = 0.003 for bipolar and P = 0.001 for unipolar affective disorder). The frequency of the low activity (short) allele was higher in patients than in controls (51.1% in bipolar, and 54.3 in unipolar vs 39.4% in controls). We suggest that the presence of allele s may increase the susceptibility to occurrence of affective disorder.