Depletion of the Human Ion Channel TRPM2 in Neuroblastoma Demonstrates Its Key Role in Cell Survival through Modulation of Mitochondrial Reactive Oxygen Species and Bioenergetics.

Transient receptor potential melastatin 2 (TRPM2) ion channel has an essential function in modulating cell survival following oxidant injury and is highly expressed in many cancers including neuroblastoma. Here, in xenografts generated from neuroblastoma cells in which TRPM2 was depleted with CRISPR/Cas9 technology and in in vitro experiments, tumor growth was significantly inhibited and doxorubicin sensitivity increased. The hypoxia-inducible transcription factor 1/2α (HIF-1/2α) signaling cascade including proteins involved in oxidant stress, glycolysis, and mitochondrial function was suppressed by TRPM2 depletion. TRPM2-depleted SH-SY5Y neuroblastoma cells demonstrated reduced oxygen consumption and ATP production after doxorubicin, confirming impaired cellular bioenergetics. In cells in which TRPM2 was depleted, mitochondrial superoxide production was significantly increased, particularly following doxorubicin. Ectopic expression of superoxide dismutase 2 (SOD2) reduced ROS and preserved viability of TRPM2-depleted cells, however, failed to restore ATP levels. Mitochondrial reactive oxygen species (ROS) were also significantly increased in cells in which TRPM2 function was inhibited by TRPM2-S, and pretreatment of these cells with the antioxidant MitoTEMPO significantly reduced ROS levels in response to doxorubicin and protected cell viability. Expression of the TRPM2 pore mutant E960D, in which calcium entry through TRPM2 is abolished, also resulted in significantly increased mitochondrial ROS following doxorubicin treatment, showing the critical role of TRPM2-mediated calcium entry. These findings demonstrate the important function of TRPM2 in modulation of cell survival through mitochondrial ROS, and the potential of targeted inhibition of TRPM2 as a therapeutic approach to reduce cellular bioenergetics, tumor growth, and enhance susceptibility to chemotherapeutic agents.

PHOX2B reliably distinguishes neuroblastoma among small round blue cell tumours.

AIMS: Neuroblastoma shows considerable histological overlap with other small round blue cell tumours. PHOX2B, a transcription factor that is essential for autonomic nervous system development, has been reported as an immunohistochemical marker for neuroblastoma. The aim of this study was to validate the specificity and diagnostic utility of PHOX2B for peripheral neuroblastic tumours. METHODS AND RESULTS: We evaluated 240 cases (133 in whole-tissue sections; 107 in tissue microarrays), including 76 peripheral neuroblastic tumours (median age 2 years; including four adults) and 164 other tumours: 44 Wilms tumours; 20 Ewing sarcomas; 10 each of CIC-rearranged round cell sarcomas, poorly differentiated synovial sarcomas, lymphoblastic lymphomas, alveolar rhabdomyosarcomas, embryonal rhabdomyosarcomas, mesenchymal chondrosarcomas, Merkel cell carcinomas, olfactory neuroblastomas, and melanomas; and five each of NUT midline carcinomas and desmoplastic small round cell tumours. Immunohistochemistry for PHOX2B was performed with a rabbit monoclonal antibody. PHOX2B positivity was defined as the presence of nuclear immunoreactivity in ≥5% of cells. PHOX2B was positive in 70 (92%) peripheral neuroblastic tumours, including 68 of 72 (94%) paediatric and two of four (50%) adult cases. Furthermore, PHOX2B was consistently negative in all non-peripheral neuroblastic tumours, with staining being absent in 160 cases and limited in four cases. CONCLUSION: PHOX2B is a highly sensitive and specific immunohistochemical marker for peripheral neuroblastic tumours, including neuroblastoma. PHOX2B reliably distinguishes neuroblastoma from histological mimics such as Wilms tumour, Ewing sarcoma, and CIC-rearranged round cell sarcoma. PHOX2B negativity in two of four adult neuroblastoma cases raises the possibility that some adult neuroblastomas are of a different lineage than paediatric cases.

Examination of PHOX2B in adult neuroendocrine neoplasms reveals relatively frequent expression in phaeochromocytomas and paragangliomas.

AIMS: Paired-like homeobox 2b (PHOX2B) is a transcription factor with expression outside of the central nervous system restricted to neurons and chromaffin cells of the autonomic nervous system. Germline mutations cause congenital central hypoventilation syndrome and predispose to neuroblastoma and Hirschsprung disease. Among paediatric small round cell tumours, PHOX2B is neuroblastoma-specific. Two studies of adult autonomic nervous system tumours (n = 62) produced conflicting results (all tumours stained in one; expression restricted to 40% of paragangliomas in the other). We examined PHOX2B expression in a large cohort of phaeochromocytomas and paragangliomas, as well as well-differentiated neuroendocrine tumours (WDNETs) and poorly differentiated neuroendocrine carcinomas (PDNECs). METHODS AND RESULTS: Tissue microarrays (TMAs) were constructed from 609 tumours: 111 phaeochromocytomas, 146 paragangliomas, 250 WDNETs, and 102 PDNECs. PHOX2B immunohistochemistry was scored for extent (%) and intensity (0-3+), and an H-score (extent × intensity) was calculated. PHOX2B expression was seen in 32% of phaeochromocytomas and in 47% of paragangliomas. Mean/median H-scores for these tumours were in the 30-55 range (i.e. weak to moderate staining). No WDNETs and only 7% of PDNECs stained, the latter often strongly. In a representative cohort of corresponding whole sections (n = 55), the results in WDNETs and PDNECs were unchanged, whereas half of the phaeochromocytomas/paragangliomas that were negative on TMAs became focally, weakly positive. CONCLUSIONS: We found frequent, weak to moderate PHOX2B expression in phaeochromocytomas/paragangliomas and no expression in WDNETs, which could be diagnostically useful in the distinction of these tumours. Expression in a minority of PDNECs probably reflects the transcription factor lineage infidelity that is characteristic of this tumour class.

Expression of LEF1 in mantle cell lymphoma.

Small lymphocytic lymphoma/chronic lymphocytic leukemia (CLL/SLL) and mantle cell lymphoma (MCL) usually are distinctly different in regard to clinical presentation, morphology, immunophenotype and molecular/genetic findings. In spite of this, select cases may show overlapping characteristics and represent a diagnostic challenge. Recently LEF1 staining was identified as a fairly characteristic finding in CLL/SLL, with positivity identified in up to 95% of cases. LEF1 staining has not been reported as being present in cases of MCL, making this stain a useful tool in distinguishing these diagnoses. We identified an index case of MCL with cyclin D1 expression and the presence of the typical t(11;14) IGH-CCND1, which expressed LEF1. Subsequently, we assessed LEF1 immunohistochemical staining in a series of 23 cases of MCL, as confirmed by staining for cyclin D1 and/or SOX11. We found expression present in one additional case, and evaluated some published literature suggesting a frequency of 4-9% expression of LEF1 by MCL. LEF1 expression by immunohistochemistry in MCL is unusual but can be seen rarely, and could represent a potential diagnostic pitfall.

N-(2,3,5,6-Tetrafluoropyridin-4-yl)formamide.

The title compound, C6H2F4N2O, displays amide bond lengths of 1.218 (3) Šand 1.366 (3) Šfor the C=O and C-N bonds, respectively. The Cp-N-C-O (p = pyridine) torsion angle of 179.0 (2)° indicates an anti-conformation for the grouping. Inter-molecular hydrogen bonding is observed between the amine N-H group and the carbonyl O atom, which generates chains of mol-ecules propagating along the b-axis direction.

Bis(1,4,7-trithia-cyclo-nona-ne)nickel(II) bis-(tetra-fluorido-borate) nitro-methane disolvate.

The homoleptic thio-ether title complex, [Ni(C(6)H(12)S(3))(2)](BF(4))(2)·2CH(3)NO(2), shows the expeced hexa-kis-(thio-ether) octa-hedral environment around the Ni(II) atom. It crystallized as two crystallographically independent complex cations, [Ni(9S3)(2)](2+) (9S3 = 1,4,7-trithia-cyclo-nona-ne), within the unit cell where each Ni(II) lies on an inversion center. In addition to the complex cations, there are two crystallographically independent BF(4) (-) anions present to balance the charge, and each shows disorder along a pseudo-C(3) axis with ratios of 0.53 (2):0.47 (2) and 0.55 (2):0.45 (2). Two nitro-methane solvent mol-ecules per complex cation are also present in the unit cell.

Ru(II) catalysts supported by hydridotris(pyrazolyl)borate for the hydroarylation of olefins: reaction scope, mechanistic studies, and guides for the development of improved catalysts.

Carbon-carbon bond formation is the central method by which synthetic chemists add complexity, which often represents value, to molecules. Uniting a carbon chain with an aromatic substrate to yield an alkyl arene product is thus a molecular means of creating value-added materials. A traditional method for generating alkyl arenes is Friedel-Crafts catalysis, in which an alkyl halide or olefin is activated to react with an aromatic substrate. Unfortunately, despite the development of new generations of solid-state catalysts, the reaction often requires relatively harsh conditions and frequently gives poor to moderate selectivity. Conversely, a halide can first be incorporated into the aromatic ring, and the aryl halide can subsequently be joined by a variety of catalytic coupling techniques. But generating the aryl halide itself can be problematic, and such methods typically are not atom-economical. The addition of aromatic C-H bonds across the C-C double bonds of olefins (olefin hydroarylation) is therefore an attractive alternative in the preparation of alkyl arenes. Despite the dominance and practical advantages of heterogeneous catalysts in industrial synthesis, homogeneous systems can offer an enhanced ability to fine-tune catalyst activity. As such, well-defined homogeneous catalysts for the hydroarylation of olefins provide a potentially promising avenue to address issues of selectivity, including the production of monoalkylated arene products and the control of linear-to-branched ratios for synthesis of long-chain alkyl arenes, and provide access to more ambient reaction conditions. However, examples of homogeneous catalysts that are active for the conversion of unactivated aromatic and olefin substrates to alkyl arene products that function via metal-mediated C-H activation pathways are limited. In this Account, we present results from research aimed at the development of Ru(II) catalysts supported by the hydridotris(pyrazolyl)borate (Tp) ligand for the addition of aromatic C-H bonds across olefins. On the basis of detailed mechanistic studies with TpRu(L)(NCMe)R catalysts, in which the neutral ancillary ligand L is varied, we have arrived at guidelines for the development of improved catalysts that are based on the octahedral-d6 motif.

Adult type rhabdomyoma presenting as a parathyroid adenoma.

BACKGROUND: Adult-type rhabdomyoma (ATR) is a rare mesenchymal tumor of skeletal muscle differentiation. Extracardiac ATR occurs most commonly in the head and neck, but do so in a heterogeneous fashion, arising at numerous different locations within this region. METHODS: At our institution, we encountered a patient who was diagnosed clinically with parathyroid adenoma based on signs and symptoms of hyperparathyroidism and suggestive radiologic findings. A parathyroidectomy with intraoperative consultation was performed. RESULTS: The frozen section diagnosis was ambiguous and a diagnosis of ATR was only made on permanent section. CONCLUSION: Awareness of this tumor can prevent incorrect diagnosis and overtreatment intraoperatively. Herein, we describe the clinical history, pathologic findings, and review histologic features of rhabdomyomas.

The Human Transient Receptor Potential Melastatin 2 Ion Channel Modulates ROS Through Nrf2.

Transient receptor potential melastatin channel subfamily member 2 (TRPM2) has an essential role in protecting cell viability through modulation of oxidative stress. TRPM2 is highly expressed in cancer. When TRPM2 is inhibited, mitochondria are dysfunctional, ROS levels are increased, and cell viability is reduced. Here, the importance of NF-E2-related factor (Nrf2) in TRPM2-mediated suppression of oxidant stress was explored. In TRPM2 depleted cells, antioxidant cofactors glutathione, NADPH, and NADH were significantly reduced. Cytoplasmic and nuclear expression of Nrf2 and of IQGAP1, a modulator of Nrf2 stability regulated by intracellular calcium, were decreased. Antioxidant enzymes transcriptionally regulated by Nrf2 and involved in GSH, NADPH, and NADH generation were significantly lower including PRX1 and PRX3, GPX4, GSTP1, GCLC, and MTHFD2. The glutamine pathway leading to GSH production was suppressed, and ATP and GTP levels were impaired. Reconstitution with wild type TRPM2 or Nrf2, but not TRPM2 pore mutant E960D, rescued expression of enzymes downstream of Nrf2 and restored GSH and GTP. Cell viability, ROS, NADPH, NADH, and ATP levels were fully rescued by TRPM2 and partially by Nrf2. These data show that TRPM2 maintains cell survival following oxidative stress through modulation of antioxidant pathways and cofactors regulated by Nrf2.

Vitamin D Toxicity: A 16-Year Retrospective Study at an Academic Medical Center.

BACKGROUND: Interest in vitamin D has increased during the past 2 decades, with a corresponding increase in laboratory testing of 25-hydroxyvitamin D [25(OH)D]. The vast majority of specimens tested display normal or deficient levels of 25(OH)D; concentrations rarely fall in the potentially toxic range. METHODS: We performed a retrospective investigation of elevated 25(OH)D levels during a 16-year period at the University of Iowa Hospitals and Clinics (UIHC), a 734-bed tertiary-/quaternary-care academic medical center in the midwestern United States. Detailed medical-record review was performed for patients with serum/plasma 25(OH)D concentrations higher than 120 ng per mL. RESULTS: A total of 127,932 serum/plasma 25(OH)D measurements were performed on 73,779 unique patients. Of these patients, 780 (1.05%) had results that exceeded 80 ng per mL and 89 patients (0.12%) had results that exceeded 120 ng per mL. Only 4 patients showed symptoms of vitamin D toxicity. Three of these cases involved inadvertent misdosing of liquid formulations. CONCLUSIONS: Symptomatic vitamin D toxicity is uncommon, and elevated levels of 25(OH)D do not strongly correlate with clinical symptoms or total serum/plasma calcium levels. Our study highlights the potential risks of the liquid formulation of vitamin D.

Use of the combined recession and resection of a rectus muscle procedure in the management of incomitant strabismus.

BACKGROUND: Scott described a method of achieving the effect of a posterior fixation procedure by combining resection and recession of a rectus muscle, while maintaining the ability to adjust primary position alignment with adjustable sutures. METHODS: A retrospective review of combined recession-resection procedures on rectus muscles between 1998 and 2002 was carried out. RESULTS: We identified 22 patients, 17 females and 5 males. The mean age at presentation was 44 years. The etiology was felt to be paralytic in seven patients (31.8%), mechanical/restrictive in seven patients (31.8%), and due to residual childhood strabismus in eight patients (36.4%). Twenty patients had undergone previous strabismus surgery, ranging from one to six operations (mean, 1.75). Scott procedures were performed on 25 rectus muscles of 22 patients; 12 on the lateral rectus muscles, 7 on the inferior rectus muscles, 3 on the medial rectus muscles, and 3 on the superior rectus muscles. All but one patient had a measurable improvement in gaze incomitance, and 11 of 12 who had a measurement of the field of binocular single vision showed improvement. Twenty patients had follow-up periods of 3 months or more, with a range of 3 to 30 months and a mean of 9.35 months. CONCLUSIONS: The combined recession-resection procedure advocated by Scott has a role in the management of incomitant strabismus.

Full-tendon nasal transposition of the vertical rectus muscles: a retrospective review.

The authors report the results of a retrospective review of patients who underwent nasal transposition of the vertical rectus muscles between 1997 and 2004. Eight patients were identified, 4 males and 4 females. There was an average age at surgery of 37 years, with a range from 8 to 79 years. The aetiologies included 6 patients with trauma to their medial rectus (4 following endoscopic sinus surgery) and 2 patients with paralytic medial rectus muscles secondary to 3rd nerve palsy. All patients underwent whole tendon transposition of the superior and inferior rectus muscles, with resection of both muscles in 7 cases, before reattachment adjacent to the upper and lower borders of the medial rectus, respectively. One patient had a reduced amount of resection and this was combined with inferior oblique disinsertion and traction sutures. All patients had a reduction in deviation in the primary position and in 5 patients there was some improvement in adduction. A consequence of surgery was a degree of limitation of abduction, elevation and depression in some patients. Overall, patients were satisfied with the improvement in their appearance.

Benefits of retroequatorial four horizontal muscle recession surgery in congenital idiopathic nystagmus in adults.

INTRODUCTION: Four muscle surgery for congenital nystagmus was originally described in 1956 and popularized by two articles in the 1990s. A review of the literature revealed only three studies of seven, nine, and six patients published since then. We therefore reviewed our patients to determine the objective and subjective benefits of this procedure. METHODS: A retrospective review was carried out on patients who underwent bilateral maximal horizontal muscle recessions for congenital nystagmus between 1997 and 2002. Improvement in visual acuity was documented. An external assessor administered an anonymized questionnaire to discover any perceived benefit. Eighteen patients were identified, 12 men and 6 women, with an average age at surgery of 32 years. RESULTS: Preoperative visual acuity ranged from 6/9 binocularly to 6/60. All underwent bilateral medial rectus muscle recessions of 8 mm to 10 mm and bilateral lateral rectus muscle recessions of 8 mm to 12 mm. Nine patients (50%) gained one line of Snellen visual acuity. There were four complications: one scleral perforation; two developed exotropia; and one complained of asthenopic symptoms. This latter patient was the only one who experienced some deterioration of vision acuity. Fourteen of 18 (78%) questionnaires were returned. Eight patients said they were pleased; four were indifferent and two were displeased. CONCLUSIONS: We conclude that this operation delivers limited objective benefit. None of our patients were able to obtain a driving license. Fifty-seven percent of patients expressed the view that they were glad to have had the surgery, although the visual improvement was only slight.

Does botulinum toxin have a role in the treatment of secondary strabismus?*.

METHODS: We reviewed the Toxin Clinic database over a 20-year period, identifying patients with strabismus secondary to permanent or temporary impairment of vision. RESULTS: Five hundred-and-three patients who fulfilled our criteria were treated with Botulinum toxin. There were 301 males and 202 females, with a mean age at treatment of 35 years (range 6-86). Three hundred-and-eighty-three patients (76%) had exotropia, 114 (22.5%) had esotropia and 6 (1.5%) had vertical strabismus. Reduced vision secondary to trauma accounted for 45% (227) of patients. Other causes were congenital anomalies 121 (24%), refractive error 30 (6%), retinal detachment 20 (4%), senile cataract 24 (5%), corneal problems 19 (4%), glaucoma 10 (2%) and other 52 (10%). One hundred-and-ninety-three (38%) were aphakic. One thousand-four-hundred-and-fifty-seven injections were given, with a range of 1-50 per patient. Ninety-nine (20%) patients were managed with continued toxin treatment. Two hundred-and-eighteen patients (43%) proceeded to surgery. Forty patients (8%) required no further treatment as they regained binocularity by injection alone. CONCLUSIONS: Botulinum toxin appears to have a role in the treatment of secondary strabismus, since only 3% (14) failed to obtain any reduction in their angle. It was well tolerated, with no permanent side effects. Only 22 (4%) patients developed ptosis.

Botulinum toxin treatment for hyperlacrimation secondary to aberrant regenerated seventh nerve palsy or salivary gland transplantation.

AIM: To investigate the potential of botulinum toxin A for treating hyperlacrimation. METHODS: Three patients with unilateral symptoms of hyperlacrimation (diagnosed as "crocodile tearing") and one patient with a submandibular salivary gland transplant (SMGT) were studied. Tear production was quantified in the resting and stimulated (chewing or following exercise) state, using Schirmer's test and tear clearance. Lacrimal scintigraphy was used to assess outflow. Intraglandular injections (for patients with "crocodile tears") or periglandular injections (for the SMGT patient) of Dysport were administered in divided doses. RESULTS: Two of the three eyes with reported gustatory lacrimation had a higher Schirmer test result than their fellow eye following gustatory stimulation. Scintigraphy, with and without stimulation, confirmed a patent drainage system in these patients. The other patient demonstrated a functional obstruction to tear flow. After treatment patients with confirmed gustatory lacrimation and the SMGT patient had a marked reduction in tearing at 2 weeks. This effect lasted 3-4 months. There was no demonstrable improvement in the patient with epiphora secondary to functional obstruction. Two patients who had received intraglandular injections developed a ptosis, which resolved spontaneously. CONCLUSIONS: This study illustrates that gustatory lacrimation is a difficult diagnosis. In post-facial nerve palsy a functional element must always be considered. However, in confirmed hyperlacrimation botulinum toxin treatment is effective but side effects may occur.

Quantitative changes in the field of binocular single vision following a fadenoperation to a vertical rectus muscle.

PURPOSE: To quantify the effect of a fadenoperation to a vertical rectus muscle on the field of binocular single vision (BSV). PATIENTS AND METHODS: BSV was assessed quantitatively in 32 patients before and after a fadenoperation to a single vertical rectus muscle by measuring the vertical extent of single vision in the midline and a score for the total field of BSV. Patients were aged from 14 to 72 years. All patients had diplopia in either downgaze or upgaze before surgery. In 11 patients, this was due to a fourth cranial nerve palsy, and in 8 patients it followed an orbital floor fracture. RESULTS: The 15 patients who had an inferior rectus fadenoperation alone showed a significant mean increase in downward and total vertical extent of BSV and in their field of BSV. The 9 patients who underwent a superior rectus fadenoperation alone showed a significant increase in total vertical extent of BSV and field of BSV score. Three of the 8 who underwent a fadenoperation combined with another strabismus procedure at the same time had a substantial improvement in their score, but after the other 5 showed little change. Patients with a paretic deficit showed substantially more improvement than those with an upgaze deficit after a blowout fracture. CONCLUSION: The fadenoperation to a vertical rectus muscle produced a significant functional expansion in the field of BSV in approximately two thirds of patients. The procedure was more effective in incomitant squints of paretic rather than mechanical etiology.

Radiotherapy in thyroid eye disease: the effect on the field of binocular single vision.

PURPOSE: Thyroid eye disease (TED) can be a functionally disabling condition if ocular muscle involvement causes diplopia. The extraocular muscle restriction creates a reduced or eccentric field of binocular single vision (BSV). Orbital radiotherapy is now widely used in the treatment of TED, and although it has been reported as improving ocular motility, there have been few quantitative studies of the effect of treatment on ocular motor function. METHODS: Retrospective case note review of patients undergoing orbital radiotherapy for TED between 1992-1998 identified 79 case records. A total of 27 patients had diplopia in primary position or a significantly reduced binocular field before undergoing radiotherapy. The fields of BSV were analyzed pretreatment and at 3, 12, and 24 months after therapy to assess any improvement in function. We used the field of BSV as an outcome measure because it can be quantified and is a good indicator of functional ability. RESULTS: None of the 12 patients with double vision in primary position pretreatment regained a central binocular field with radiotherapy alone. Of the 15 patients with a central but reduced binocular field, 8 (53%) remained unchanged with treatment. In 4 patients (26.6%), there was an improvement in the field, while in 3 (20%) the field deteriorated. In all, 12 patients (44%) went on to require strabismus surgery. CONCLUSIONS: Orbital radiotherapy alone is ineffective in treating restrictive thyroid myopathy and improving binocular function.

The use of botulinum toxin to treat strabismus following retinal detachment surgery.

METHODS: Persistent symptomatic strabismus may be seen in up to 25% of patients post retinal detachment surgery. Surgical correction of ocular misalignment in this situation can be technically difficult to perform and the results are less predictable than in other forms of strabismus surgery. We report on our experience of the use of botulinum toxin injections as an alternative. RESULTS: A retrospective review was made of all patients who had received botulinum toxin injections in the management of their strabismus following retinal detachment surgery at our institution between November 1982 and January 2006. One hundred and forty patients fulfilled our criteria with a mean length of follow-up of 27 months. Thirty-three patients (23.6%) were symptom free following botulinum toxin injection alone and were discharged from the clinic, 50.5% of these after only 2 injections. Fusion was regained in 37.9%. The only factor associated with lack of restoration of fusion in the multivariate analysis was visual acuity in the injected eye. Complications were seen in 2.9% of patients. CONCLUSION: Botulinum toxin injections may represent a safe and acceptable alternative to surgery and may be particularly useful for those in whom surgery is contraindicated or not desired.

Beneficial effect of treatment for strabismus in patients with bilaterally poor vision, who cannot see their strabismus.

METHODS: Retrospective case note review of management of patients with bilaterally severely reduced vision presenting with symptomatic strabismus. RESULTS: There were 10 females and 7 males, mean age at treatment was 36 years, range 19 to 74 years. Thirteen patients had an exotropia ranging from 20 to 90(Δ) (mean 52(Δ)). Four had an esotropia ranging from 30 to 70(Δ) (mean 53(Δ)). Vision in each eye ranged from 6/24 Snellen to light perception, except for one patient with Usher's syndrome who had grossly restricted visual fields and vision of 6/12 and 6/36. The etiology was retinitis pigmentosa in 5 patients; 3 had cone dystrophy, 2 were high myopes. Other etiologies included CMV retinitis in both eyes secondary to HIV, bilateral optic atrophy post craniopharyngioma, and cortical visual impairment. All patients were unable to see well enough to assess their strabismus but were aware of its presence from family members and friends and wished improvement. Eleven patients underwent botulinum toxin injections; 2 of these then proceeded to surgery. A total of 8 patients had surgery. Post-operative angles ranged from 6(Δ) to 25(Δ) of esotropia. Five patients continue with maintenance toxin. Follow-up ranged from 3 months to 15 years. DISCUSSION/CONCLUSIONS: This is the first report of patients with bilaterally severely reduced vision requesting treatment for strabismus that they were unable to see for themselves. All patients were pleased they had undergone treatment for their strabismus despite being unable to see the outcome.

Role of inferior rectus botulinum toxin injection in vertical strabismus resulting from orbital pathology.

INTRODUCTION: We describe the uses and efficacy of botulinum toxin injection to the inferior rectus muscle in vertical strabismus resulting from orbital pathology. METHODS: A retrospective review of patients undergoing inferior rectus botulinum toxin injection between 1982 and 2006 for vertical strabismus due to orbital pathology. RESULTS: There were 13 patients identified; 6 with idiopathic orbital inflammatory syndrome (IOIS) including myositis, 3 with previous orbital wall fractures, 1 post-optic nerve sheath Schwannoma resection, 1 with lymphoma, 1 with metastasis, and 1 post-superior ophthalmic vein hemorrhage. A beneficial effect with inferior rectus botulinum toxin was obtained in 9/13 (69%) patients (mean follow-up 14 months). Resolution or improvement occurred in 4/6 (67%) patients with IOIS. Resolution was also obtained in the patient with previous optic nerve sheath Schwannoma resection, and the patient who sustained the superior ophthalmic vein hemorrhage. Improvement was noted in both the patient with lymphoma and in the patient with a metastasis. However, in patients with orbital wall fractures, only 1 of 3 patients obtained improvement. Benefit appeared independent of the size of vertical deviation, with 4/6 (67%) showing improvement with a pre-toxin angle 4-12 PD, and 5/7 (71%) improving with a pre-toxin angle 16-25 PD. Eleven patients received only 1 injection, one patient received 2, and another had an ongoing course of 8 injections. DISCUSSION: Vertical strabismus secondary to a range of orbital conditions, particularly inflammatory, often can be successfully managed by inferior rectus botulinum toxin injections.