Botulinum toxin type A in multimodal management of age-related macular degeneration and related diseases.

Age related macular degeneration (AMD) is the major cause of visual loss in the aging population in the Western world. In past decade, intra ocular injections of anti-vascular endothelial growth factor (anti-VEGF) pharmaceuticals have revolutionized therapy for exudative (edematous-wet) AMD and become standard practice for the near term. However repeated intra-ocular injections are required for years and long terms results have been limited. The pathogenesis of this condition is multifactorial involving genetic, ischemic, inflammatory factors leading to neovascularization, edema and retinal pigment epithelial scaring resulting in photoreceptor destruction. Based on coincidental observation in reduction in AMD related macular edema on ocular coherence tomography (OCT) in a BoNT A treated patient with facial movement disease, BoNT-A at conventional doses targeting the para orbital area was added to therapeutic regiment in a small number of patients with exudative macular degeneration or related diseases. Measurements of edema and choriocapillaris using Spectral Doman (OCT) and Ocular Coherence Angiography (OCT-A) and Snellen visual acuity were made over the evaluation period. 15 eyes in 14 patients averaged 361 µm central sub foveal edema (CSFT) pre injection and average of 266 µm (CSFT) post injection over an average of 21 months and 5.7 cycles using BoNT A alone at conventional doses (n = 86 post injection measurements, paired t-test p < 0.001 two tailed). Visions at baseline in patients with 20/40 or worse averaged 20/100- pre injection improved to an average of 20/40- in the post injection period (n = 49 measurements p < 0.002 paired t-test). The previous data was added to a group of 12 more severely afflicted patients receiving anti VEGF (aflibercept or bevacizumab) (total 27 patients). With this 27-patient group, patients were followed for an average of 20 months and receiving average of 6 cycles at conventional doses. Improvement in exudative edema and vision were noted with pre injection baseline CSFT average 399.5, post injection average 267, n = 303 post measurement, independent t-test P < 0.0001.). Snellen vision 20/128 baseline average improved to average of 20/60- during post injection period (n = 157 post injection measurements, p < 0.0001 paired t-test to baseline). No substantial adverse effects were noted. Cyclic effects were noted corresponding to duration of action of BoNT-A on a number of patients. The above data is preliminary and is skewed toward early leakage for all conditions. BoNT A may have a role in the treatment of aged related macular degeneration. Controlled studies are needed with careful staging and baseline stratifications for multi-modal management paradigms. The findings are discussed relative to known botulinum toxin type A pharmacology and AMD pathogenesis.

Multiple Eyelid Cysts (Apocrine and Eccrine Hidrocystomas, Trichilemmal Cyst, and Hybrid Cyst) in a Patient With a Prolactinoma.

A 53-year-old man presented with smooth-domed, variegated cysts (polycystic disease) of all 4 eyelids, worse on the left side. Some of the cysts were clear, while others were creamy-white colored. In addition, multiple, very fine vesicopapules were noted along the eyelid margins. Histopathologic examination revealed a trichilemmal cyst, several pure apocrine hidrocystomas displaying multiple chambers, a hybrid cyst, and many small eccrine cysts of the deep dermis. The apocrine lesions, including the small ones at the eyelid margins, predominated. Smooth muscle actin sometimes positively stained outer myoepithelial cells in some of the apocrine cysts, which helped to distinguish them from eccrine cysts. Most noteworthy was the fact that the patient had been diagnosed with a prolactinoma 20 years earlier. There is only 1 previous report of multiple apocrine cysts and an antecedent prolactinoma in the dermatologic literature. This syndrome should be separated from that of Schöpf-Schulz-Passarge, which manifests multiple small eyelid apocrine cysts and other ectodermal dysplasias without any association with neoplasia, and from that of focal dermal hypoplasia (Goltz-Gorlin) syndrome with apocrine cysts but again without neoplasia.

Parry-Romberg syndrome vasculopathy and its treatment with botulinum toxin.

Parry-Romberg syndrome is a rare condition characterized by progressive, hemifacial atrophy, hair loss, enophthalmos, retinal vasculopathy occasionally associated with hemicranial pain syndrome (secondary trigeminal neuralgia). The cause of the condition is unknown; however, substantial evidence suggests that vasculopathy plays a significant role in the genesis of the neurologic damage and facial lipodystrophy. Herein describes a case of Parry-Romberg syndrome treated with repetitive botulinum type A toxin injections, with almost complete resolution of severe chronic pain.

Use of fillers as adjunct therapy for the treatment of lower face hemifacial spasm.

The treatment of hemifacial spasm with periorbital injections of higher doses of botulinum toxin can create disfiguring and undesirable weakness in the lower face during active facial movements. The use of asymmetric hyaluronidate filler injections to the lower face provides a refinement allowing for a lowered neurotoxin dose. The filler creates a ballasting effect and involuntary facial movement. The conventional filler effect also further reduces asymmetric nasolabial folds and marionette lines. Fifteen of 18 patients with lower facial spasms found the filler toxin combination an improvement over neurotoxin alone.

Desmoplastic trichoepithelioma: report of a unique periocular case.

In a 58-year-old woman with blepharospasm, a slowly enlarging left inferomedial eyelid lesion developed. It measured 3 × 5 mm and was nonulcerated, well-circumscribed, whitish, upraised, and firm. An initial incomplete excision followed by a total repeated excision revealed small squamous microcysts, often exhibiting calcifications and cords of nonclefting basaloid cells embedded in a scirrhous stroma characteristic of desmoplastic trichoepithelioma (DTE). Immunohistochemical investigations disclosed CD34-positive stromal fibroblasts and many CK20-positive Merkel cells located among the epithelial cells, features absent in mimicking sclerosing basal cell carcinoma (BCC). The tumor has not recurred during 6 months of follow up. Besides BCC, the differential diagnosis chiefly concerns syringoma and microcystic adnexal carcinoma. Surgical therapy should aim at complete excision but does not have to be as extensive or aggressive as that used for morpheic or sclerosing BCC because of its lack of diffusely infiltrating margins.

Drug-induced graves disease from CTLA-4 receptor suppression.

Monoclonal antibody, ipilimumab, useful for treatment of metastatic melanoma, blocks CTLA-4 mediated T-cell suppression and can also cause a Graves ophthalmopathy like syndrome. Epidemiologic study has linked variant polymorphisms of CTLA-4 receptor gene to the presence of thyroid eye disease. The combination of these observations suggests CTLA-4 mediated T-cell functions are important to the pathogenesis of thyroid-associated eye disease.

Orbicularis oculi myo-osseous fixation: a new treatment for benign essential blepharospasm and blepharospasm associated with diffuse facial dystonia (meige syndrome).

BACKGROUND AND OBJECTIVE: This article describes a novel surgical procedure, myo-osseous fixation, as an adjunct therapy for patients with reduced or poor response to repeated botulinum toxin injections for essential blepharospasm and Meige syndrome. PATIENTS AND METHODS: The small-incision, rapidly healing, rapidly performed technique uses self-drilling titanium screws tightly engaged with a compression wrench. The screws fixate the periorbital orbicularis oculi muscle to bone, creating mechanical resistance to outer portions of the orbicularis muscle involved in debilitating involuntary contractions. RESULTS: Eleven of the treated 12 patients experienced immediate improvement in function. Each responding patient noted enhanced effect of subsequent botulinum toxin injections at previously ineffective doses. The benefit was substantial and sustained for 6 months in 9 of 12 patients. Decreased brow depression during forced closure, forced frown, and brow elevation at rest was apparent in all patients postoperatively. Although the brow elevation effect was reduced after 6 months, reduced brow depression during forced closure still was easily demonstrated in most patients. Complications included a nodular bump over the brow, more commonly found when large titanium screws were used, transient headache, and easily removed dislodged screw. CONCLUSION: Initial data suggest that this procedure appears safe, well tolerated, and useful in the treatment of patients with essential blepharospasm and Meige syndrome responding poorly to botulinum toxin therapy.

A neuronal cell-based botulinum neurotoxin assay for highly sensitive and specific detection of neutralizing serum antibodies.

Clostridium botulinum neurotoxin (BoNT) serotypes A and B are widely used as pharmaceuticals to treat various neurological disorders and in cosmetic applications. The major adverse effect of these treatments has been resistance to treatment after multiple injections. Currently, patients receiving BoNT therapies and patients enrolled in clinical trials for new applications and/or new formulations of BoNTs are not routinely monitored for the formation of neutralizing antibodies, since no assay other than the mouse protection procedure is commercially available that reliably tests for the presence of such antibodies. This report presents a highly sensitive and specific neuronal cell-based assay that provides sensitive and specific detection of neutralizing antibodies to BoNT/A.

Botulinum toxin, immunologic considerations with long-term repeated use, with emphasis on cosmetic applications.

Botulinum toxin is a unique pharmaceutical agent in wide-scale use for cosmetic and multiple therapeutic applications. Physicians using these agents for esthetic purpose must realize the potential for future therapeutic needs. Because most indications require repeated injections, the recipient is at risk for immunologic reactions with possible formation of neutralizing antibodies. An individual who is injected with botulinum toxin for cosmetic purposes could someday require an effective form of type A toxin for dystonia, pain, or spasticity.

Botulinum toxin for aberrant facial nerve regeneration: double-blind, placebo-controlled trial using subjective endpoints.

BACKGROUND: Aberrant facial nerve regeneration syndrome is systematically studied by constructing a subjective questionnaire organized into pertinent domains (impairment of quality of life, social interactions, perception of self-appearance, visual function, and perception of problem severity) and by physical assessment of degree of involuntary palpebral fissure closure during routine facial movements using videotaping and a physicians' grading scale. METHODS: The videotape measurements of corneal light reflex to upper lid margin distance and vertical palpebral distance were made during adynamic and active facial expression. Thirty-six patients were studied (six in an open-label pilot study design and 30 in a multicenter, double-blind, placebo-controlled trial). Botulinum toxin type A injections consistently suppressed the degree of involuntary eyelid movement associated with smiling, chewing, and puckering by each measurement and in both study designs. RESULTS: In all subjective morbidity domains, improvement was demonstrated in the double-blind study design (quality of life, p < 0.05; social interaction, p < 0.001; personal appearance, p < 0.001; peripheral visual impairment, p < 0.01; and perception of severity, p < 0.05). Correlation between degrees of physical impairment was significant but low comparing degree of subjective impairment to direct videotaped measurements. Correlation was more significant comparing subjective scores to the physicians' grading scale assessment of degree of physical impairment. CONCLUSIONS: Impairment in quality of life, social interactions, and self-assessment of appearance closely reflected the nature of the morbidity associated with palpebral fissure asymmetry associated with aberrant facial nerve regeneration. The physicians' grading scale best reflected subjective morbidity over direct videotaped measurements.

The use of botulinum toxin for the treatment of chronic facial pain.

An open label pilot study was conducted to evaluate efficacy of botulinum toxin injections for the treatment of patients with chronic facial pain seeking tertiary care at a pain clinic. Diagnoses included temporomandibular joint syndrome, postsurgical pain syndromes, essential headache, and idiopathic trigeminal neuralgia. Thirty-three (75%) of 44 patients favorably responded, including 8 of 11 patients with trigeminal neuralgia. The duration of beneficial effect ranged from 2 to 4 months, and all responding patients desired further injections. Complications were mild and included temporary facial asymmetry and weakness secondary to neuromuscular effects of botulinum toxin. Doses ranged from 25 to 75 LD 50 units with Hall strain-derived botulinum toxin type A. A small degree of facial edema during pain or erythema seemed to have predictive value when categorically evaluated against response.