Therapeutic benefit of idebenone in patients with Leber hereditary optic neuropathy: The LEROS nonrandomized controlled trial.

Leber hereditary optic neuropathy (LHON) is a mitochondrial disease leading to rapid and severe bilateral vision loss. Idebenone has been shown to be effective in stabilizing and restoring vision in patients treated within 1 year of onset of vision loss. The open-label, international, multicenter, natural history-controlled LEROS study (ClinicalTrials.gov NCT02774005) assesses the efficacy and safety of idebenone treatment (900 mg/day) in patients with LHON up to 5 years after symptom onset (N = 199) and over a treatment period of 24 months, compared to an external natural history control cohort (N = 372), matched by time since symptom onset. LEROS meets its primary endpoint and confirms the long-term efficacy of idebenone in the subacute/dynamic and chronic phases; the treatment effect varies depending on disease phase and the causative mtDNA mutation. The findings of the LEROS study will help guide the clinical management of patients with LHON.

Indirect Comparison of Lenadogene Nolparvovec Gene Therapy Versus Natural History in Patients with Leber Hereditary Optic Neuropathy Carrying the m.11778G>A MT-ND4 Mutation.

INTRODUCTION: Lenadogene nolparvovec is a promising novel gene therapy for patients with Leber hereditary optic neuropathy (LHON) carrying the m.11778G>A ND4 mutation (MT-ND4). A previous pooled analysis of phase 3 studies showed an improvement in visual acuity of patients injected with lenadogene nolparvovec compared to natural history. Here, we report updated results by incorporating data from the latest phase 3 trial REFLECT in the pool, increasing the number of treated patients from 76 to 174. METHODS: The visual acuity of 174 MT-ND4-carrying patients with LHON injected in one or both eyes with lenadogene nolparvovec from four pooled phase 3 studies (REVERSE, RESCUE and their long-term extension trial RESTORE; and REFLECT trial) was compared to the spontaneous evolution of an external control group of 208 matched patients from 11 natural history studies. RESULTS: Treated patients showed a clinically relevant and sustained improvement in their visual acuity when compared to natural history. Mean improvement versus natural history was - 0.30 logMAR (+ 15 ETDRS letters equivalent) at last observation (P < 0.01) with a maximal follow-up of 3.9 years after injection. Most treated eyes were on-chart as compared to less than half of natural history eyes at 48 months after vision loss (89.6% versus 48.1%; P < 0.01) and at last observation (76.1% versus 44.4%; P < 0.01). When we adjusted for covariates of interest (gender, age of onset, ethnicity, and duration of follow-up), the estimated mean gain was - 0.43 logMAR (+ 21.5 ETDRS letters equivalent) versus natural history at last observation (P < 0.0001). Treatment effect was consistent across all phase 3 clinical trials. Analyses from REFLECT suggest a larger treatment effect in patients receiving bilateral injection compared to unilateral injection. CONCLUSION: The efficacy of lenadogene nolparvovec in improving visual acuity in MT-ND4 LHON was confirmed in a large cohort of patients, compared to the spontaneous natural history decline. Bilateral injection of gene therapy may offer added benefits over unilateral injection. TRIAL REGISTRATION NUMBERS: NCT02652780 (REVERSE); NCT02652767 (RESCUE); NCT03406104 (RESTORE); NCT03293524 (REFLECT); NCT03295071 (REALITY).

Safety of Lenadogene Nolparvovec Gene Therapy Over 5 Years in 189 Patients With Leber Hereditary Optic Neuropathy.

PURPOSE: To evaluate the safety profile of lenadogene nolparvovec (Lumevoq) in patients with Leber hereditary optic neuropathy. DESIGN: Pooled analysis of safety data from 5 clinical studies. METHODS: A total of 189 patients received single unilateral or bilateral intravitreal injections of a recombinant adeno-associated virus 2 (rAAV2/2) vector encoding the human wild-type ND4 gene. Adverse events (AEs) were collected throughout the studies, up to 5 years. Intraocular inflammation and increased intraocular pressure (IOP) were ocular AEs of special interest. Other assessments included ocular examinations, vector bio-dissemination, and systemic immune responses against rAAV2/2. RESULTS: Almost all patients (95.2%) received 9 × 1010 viral genomes and 87.8% had at least 2 years of follow-up. Most patients (75.1%) experienced at least one systemic AE, but systemic treatment-related AEs occurred in 3 patients; none were serious. Intraocular inflammation was reported in 75.6% of lenadogene nolparvovec-treated eyes. Almost all intraocular inflammations occurred in the anterior chamber (58.8%) or in the vitreous (40.3%), and were of mild (90.3%) or moderate (8.8%) intensity; most resolved with topical corticosteroids alone. All IOP increases were mild to moderate in intensity. No AE led to study discontinuation. Bio-dissemination of lenadogene nolparvovec and systemic immune response were limited. The safety profile was comparable for patients treated bilaterally and unilaterally. CONCLUSIONS: Lenadogene nolparvovec had a good overall safety profile with excellent systemic tolerability, consistent with limited bio-dissemination. The product was well tolerated, with mostly mild ocular side effects responsive to conventional ophthalmologic treatments.

Randomized trial of bilateral gene therapy injection for m.11778G>A MT-ND4 Leber optic neuropathy.

Leber hereditary optic neuropathy (LHON) is an important example of mitochondrial blindness with the m.11778G>A mutation in the MT-ND4 gene being the most common disease-causing mtDNA variant worldwide. The REFLECT phase 3 pivotal study is a randomized, double-masked, placebo-controlled trial investigating the efficacy and safety of bilateral intravitreal injection of lenadogene nolparvovec in patients with a confirmed m.11778G>A mutation, using a recombinant adeno-associated virus vector 2, serotype 2 (rAAV2/2-ND4). The first-affected eye received gene therapy; the fellow (affected/not-yet-affected) eye was randomly injected with gene therapy or placebo. The primary end point was the difference in change from baseline of best-corrected visual acuity (BCVA) in second-affected/not-yet-affected eyes treated with lenadogene nolparvovec versus placebo at 1.5 years post-treatment, expressed in logarithm of the minimal angle of resolution (LogMAR). Forty-eight patients were treated bilaterally and 50 unilaterally. At 1.5 years, the change from baseline in BCVA was not statistically different between second-affected/not-yet-affected eyes receiving lenadogene nolparvovec and placebo (primary end point). A statistically significant improvement in BCVA was reported from baseline to 1.5 years in lenadogene nolparvovec-treated eyes: -0.23 LogMAR for the first-affected eyes of bilaterally treated patients (P < 0.01); and -0.15 LogMAR for second-affected/not-yet-affected eyes of bilaterally treated patients and the first-affected eyes of unilaterally treated patients (P < 0.05). The mean improvement in BCVA from nadir to 1.5 years was -0.38 (0.052) LogMAR and -0.33 (0.052) LogMAR in first-affected and second-affected/not-yet-affected eyes treated with lenadogene nolparvovec, respectively (bilateral treatment group). A mean improvement of -0.33 (0.051) LogMAR and -0.26 (0.051) LogMAR was observed in first-affected lenadogene nolparvovec-treated eyes and second-affected/not-yet-affected placebo-treated eyes, respectively (unilateral treatment group). The proportion of patients with one or both eyes on-chart at 1.5 years was 85.4% and 72.0% for bilaterally and unilaterally treated patients, respectively. The gene therapy was well tolerated, with no systemic issues. Intraocular inflammation, which was mostly mild and well controlled with topical corticosteroids, occurred in 70.7% of lenadogene nolparvovec-treated eyes versus 10.2% of placebo-treated eyes. Among eyes treated with lenadogene nolparvovec, there was no difference in the incidence of intraocular inflammation between bilaterally and unilaterally treated patients. Overall, the REFLECT trial demonstrated an improvement of BCVA in LHON eyes carrying the m.11778G>A mtDNA mutation treated with lenadogene nolparvovec or placebo to a degree not reported in natural history studies and supports an improved benefit/risk profile for bilateral injections of lenadogene nolparvovec relative to unilateral injections.

Real-World Clinical Experience With Idebenone in the Treatment of Leber Hereditary Optic Neuropathy.

BACKGROUND: Leber hereditary optic neuropathy (LHON) leads to bilateral central vision loss. In a clinical trial setting, idebenone has been shown to be safe and to provide a trend toward improved visual acuity, but long-term evidence of effectiveness in real-world clinical practice is sparse. METHODS: Open-label, multicenter, retrospective, noncontrolled analysis of long-term visual acuity and safety in 111 LHON patients treated with idebenone (900 mg/day) in an expanded access program. Eligible patients had a confirmed mitochondrial DNA mutation and had experienced the onset of symptoms (most recent eye) within 1 year before enrollment. Data on visual acuity and adverse events were collected as per normal clinical practice. Efficacy was assessed as the proportion of patients with either a clinically relevant recovery (CRR) or a clinically relevant stabilization (CRS) of visual acuity. In the case of CRR, time to and magnitude of recovery over the course of time were also assessed. RESULTS: At time of analysis, 87 patients had provided longitudinal efficacy data. Average treatment duration was 25.6 months. CRR was observed in 46.0% of patients. Analysis of treatment effect by duration showed that the proportion of patients with recovery and the magnitude of recovery increased with treatment duration. Average gain in best-corrected visual acuity for responders was 0.72 logarithm of the minimal angle of resolution (logMAR), equivalent to more than 7 lines on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. Furthermore, 50% of patients who had a visual acuity below 1.0 logMAR in at least one eye at initiation of treatment successfully maintained their vision below this threshold by last observation. Idebenone was well tolerated, with most adverse events classified as minor. CONCLUSIONS: These data demonstrate the benefit of idebenone treatment in recovering lost vision and maintaining good residual vision in a real-world setting. Together, these findings indicate that idebenone treatment should be initiated early and be maintained more than 24 months to maximize efficacy. Safety results were consistent with the known safety profile of idebenone.

The Predictive Role of Intraoperative Visual Evoked Potentials in Visual Improvement After Endoscopic Pituitary Tumor Resection in Large and Complex Tumors: Description and Validation of a Method.

BACKGROUND: With the advent of extensive endoscopic approaches for pituitary tumors, there has also been an increase in surgery for larger and more complex tumors. Intraoperative manipulation during endoscopic resection of sellar tumors poses potential risk in postoperative visual function in this tumor population. This study proposes a method of accurate intraoperative monitoring of visual evoked potentials (VEPs) and its role in predicting visual function outcomes. METHODS: Intraoperative VEPs were monitored for 42 resections from a single surgical team, with average tumor size of 2.84 cm. Changes in VEP amplitude and latency in excess of 50% were considered significant. Preoperative and postoperative visual information was obtained from ophthalmology and hospital records, along with patient demographics, comorbidities, and tumor characteristics. RESULTS: Patients were stratified as experiencing deteriorations in VEPs that did not restore to baseline (n = 4), deteriorations in VEPs that did restore to baseline (n = 6), no change in VEPs (n = 31), and improvement in VEPs (n = 1). Correlation between VEP changes and postoperative visual fields was measured through univariate ordered logistic regression. Improved intraoperative VEP measurements were associated with odds ratio (OR) of visual field improvement of 3.15 (95% confidence interval, 1.15-8.59). Specifically, changes in VEP amplitude were positively associated with visual field improvement with OR of 4.35 (OR, 1.29-14.7). No association was observed between VEPs and other patient or tumor characteristics. CONCLUSION: Changes in VEP amplitude during endoscopic sellar tumor resection correlate with postoperative visual function. Intraoperative VEP monitoring can serve an important role in preventing postoperative visual field loss.

The Effect of Acetazolamide and Weight Loss on Intraocular Pressure in Idiopathic Intracranial Hypertension Patients.

PURPOSE: Acetazolamide (ACZ) lowers intraocular pressure (IOP), acutely in normal eyes and both acutely and chronically in eyes with glaucoma, and cerebrospinal fluid pressure (CSFp), chronically in patients with idiopathic intracranial hypertension (IIH). We hypothesize chronic daily ACZ would significantly reduce IOP and contribute to a translaminar pressure gradient change reflected by alteration in the CSFp-IOP difference and the deformation of the neural canal in patients with IIH and no glaucoma. PATIENTS AND METHODS: Before randomization to ACZ or placebo treatment for 6 months, 165 participants in the IIH Treatment Trial had evaluations that included Goldmann applanation, CSFp measurement, and optical coherence tomography determination of the neural canal deformation. These measures were repeated at the 6-month outcome. RESULTS: The IOP was not significantly decreased from baseline at 1, 3, or 6 months in eyes in both treatment groups. At month 6, the amount of ACZ or weight modification did not correlate with any IOP change. The 6-month mean change in neural canal deformation was 0.96 and -0.04 (P=0.001) and in CSFp was -128 and -38 mm H2O (P=0.001), but CSFp-IOP difference change was not significant, in the ACZ and placebo groups, respectively. CONCLUSIONS: ACZ does not reduce the IOP in eyes without glaucoma but does decrease the pathologic elevated CSFp, providing evidence that normal systems can compensate for chronic medication effects. The CSFp-IOP is not a direct marker of translaminar pressure gradient and the ACZ normalization of the neural canal deformation appears due to CSFp reduction alone.

Validity and Acceptance of Color Vision Testing on Smartphones.

BACKGROUND: Ishihara color plates (ICP) are the most commonly used color vision test (CVT) worldwide. With the advent of new technologies, attempts have been made to streamline the process of CVT. As hardware and software evolve, smartphone-based testing modalities may aid ophthalmologists in performing more efficient ophthalmic examinations. We assess the validity of smartphone color vision testing (CVT) by comparing results using the Eye Handbook (EHB) CVT application with standard Ishihara color plates (ICP). METHODS: Prospective case-control study of subjects 18 years and older with visual acuity of 20/100 or better at 14 inches. The study group included patients with any ocular pathology. The color vision deficient (CVD) group was patients who failed more than 2 plates. The control group had no known ocular pathology. CVT was performed with both ICP and EHB under standardized background illuminance. Eleven plates were tested with each modality. Validity of EHB CVT and acceptance of EHB CVT were analyzed. Statistical analyses were performed using Bland-Altman plot with limits of agreement (LOA) at the 95th percentile of differences in score, independent samples t tests with 95% confidence interval (CI), and Pearson χ tests. RESULTS: The Bland-Altman plot showed agreement between correct number of plates in EHB and ICP for the study subjects (bias, -0.25; LOA, -1.92 to 1.42). Agreement was also observed between the correct number of plates in EHB and ICP for the controls (bias, -0.01; LOA, -0.61 to 0.59) and CVD (bias, -0.50; LOA, -4.64 to 3.64) subjects. The sensitivity of EHB was 0.92 (95% CI 0.76-1.07) and the specificity of EHB was 1.00 (95% CI 1.00-1.00). Fifty-nine percent preferred EHB, 12% preferred ICP, and 29% had no preference. CONCLUSIONS: In healthy controls and patients with ocular pathology, there was an agreement of CVT results comparing EHB with ICP. Overall, the majority preferred EHB to ICP. These findings demonstrate that further testing is required to understand and improve the validity of smartphone CVT in subjects with ocular pathology.

Optical Coherence Tomography in the Management of Skull Base Fibrous Dysplasia with Optic Nerve Involvement.

BACKGROUND: Fibrous dysplasia (FD) of the skull base can manifest with optic nerve compression. As most patients initially do not experience vision loss, controversy exists whether to proceed with prophylactic surgical decompression or elect for conservative observation. Optical coherence tomography (OCT), a physiologic imaging modality widely used to assess the condition of the retinal nerve fiber layer (RNFL), has been useful in monitoring compressive tumors on the optic nerve. This study evaluated potential use of OCT in management of patients with fibrous dysplasia and optic nerve involvement. METHODS: Six patients with suspected optic nerve compression who underwent OCT imaging as part of a neuro-ophthalmic examination were reviewed over a 2-year period. Patient records were evaluated for visual examination measures, most notably the presence of optic neuropathy, and radiographic measures on computed tomography. Measures were compared by age-adjusted RNFL thickness (above or below fifth percentile) on OCT imaging. RESULTS: Two patients were found to have mild optic neuropathy in 1 eye each. Three of 12 eyes fell below the age-adjusted fifth percentile of RNFL thickness. Presence of optic neuropathy was associated with abnormal age-adjusted RNFL thickness but not with optic nerve compression (P = 0.45). CONCLUSIONS: Abnormal RNFL thickness as measured by OCT better predicted the presence of optic neuropathy than computed tomography alone. OCT may be a valuable imaging modality to monitor patients with fibrous dysplasia for development of optic neuropathy during periods of conservative watchful waiting.

Relationship Between Optic Nerve Head Drusen Volume and Structural and Functional Optic Nerve Damage.

PURPOSE: The purpose of this study is to assess the relationships between optic nerve head drusen (ONHD) volume, retinal nerve fiber layer (RNFL) thickness and visual field (VF) loss. METHODS: Patients with ONHD and no other ocular or systemic conditions that can affect RNFL or VF were enrolled. Serial enhanced depth imaging (EDI) optical coherence tomography (OCT) B-scans of the optic nerve head (interval between scans, ~30 µm) were obtained from each participant. ONHD volume was calculated for each eye by delineating the ONHD masses in each OCT B-scan using 3-dimensional reconstruction software. RESULTS: A total of 47 eyes (28 patients) with ONHD were included (mean age, 57±16 y). ONHD volume varied considerably [0.265±0.227 (range, 0.005 to 0.855)] mm. Linear and quadratic regression analyses demonstrated that ONHD volume is significantly associated with both global average RNFL thickness (linear R=0.531, quadratic R=0.557; P<0.001) and VF mean deviation (linear R=0.519, quadratic R=0.522; P<0.001). ONHD were most prevalent in the nasal quadrant (46 eyes, 98%), followed by superior, inferior and temporal quadrants [35 (74%), 30 (64%), and 16 (34%) eyes respectively]. The proportion of eyes with OCT RNFL defects (81%; 38/47 eyes) was significantly greater than that with VF defects (60%; 28/47 eyes) (P<0.001). RNFL defects were detected in 10 of the 19 eyes with no VF defects. RNFL defects were detected in all 28 eyes with VF defects. CONCLUSIONS: ONHD volume generally correlates with structural and functional optic nerve damage.

Ipsilateral Ophthalmic and Cerebral Infarctions After Cosmetic Polylactic Acid Injection Into the Forehead.

A 55-year-old woman developed no light perception vision in her right eye 5 days after an injection of polylactic acid cosmetic filler into her right forehead. Diffuse corneal edema and anterior chamber inflammation prohibited any view to the posterior segment to identify the cause of her profound vision loss. MRI of the orbits with diffusion-weighted imaging showed hyperintensity of the right optic nerve with signal reduction on apparent diffusion coefficient mapping, consistent with ischemia. Our patient also was found to have acute infarctions in the distribution of the right anterior cerebral artery on MRI of the brain despite having no permanent focal neurologic deficits aside from vision loss.

Pilot Study on Early Postoperative Discharge in Pituitary Adenoma Patients: Effect of Socioeconomic Factors and Benefit of Specialized Pituitary Centers.

Introduction Pituitary neoplasms are benign entities that require distinct diagnostic and treatment considerations. Recent advances in endoscopic transsphenoidal surgery have resulted in shorter lengths of stay (LOS). We implemented a postoperative day (POD) 1 discharge paradigm involving a multidisciplinary approach and detailed preoperative evaluation and review of both medical and socioeconomic factors. Methods The experience of a single neurosurgeon/ears, nose, throat (ENT) team was reviewed, generating a preliminary retrospective database of the first 30 patients who underwent resection of pituitary lesions under the POD 1 discharge paradigm. We assessed multiple axes from their preoperative, in-house, and postoperative care. Results There were 14 men and 16 women with an average age of 53.8 years (range: 27-76 years). There were 22 nonsecretory and 8 secretory tumors with average size of 2.80 cm (range: 1.3-5.0 cm). All 30 patients underwent preoperative ENT evaluation. Average LOS was 1.5 ± 0.7 days. A total of 18 of 30 patients were discharged on POD 1. The insurance status included 15 with public insurance such as emergency Medicaid and 15 with private insurance. Four patients had transient diabetes insipidus (DI); none had permanent DI. Overall, 28 of 30 patients received postoperative steroids. Factors that contributed to LOS > 1 day included public insurance status, two or more medical comorbidities, diabetes mellitus, transient panhypopituitarism, and DI. Conclusion The implementation of a POD 1 discharge plan for pituitary tumors is feasible and safe for elective patients. This implementation requires the establishment of a dedicated Pituitary Center model with experienced team members. The consistent limitation to early discharge was socioeconomic status. Efforts that incorporate the analysis of social disposition parameters with proper management of clinical sequelae are crucial to the maintenance of ideal LOS and optimal patient outcomes.

Structure and clinical significance of central optic disc pits.

OBJECTIVE: To assess the structure of central optic disc pits (ODPs) using enhanced-depth imaging optical coherence tomography (EDI OCT) and to ascertain their clinical significance. DESIGN: Prospective, cross-sectional study. PARTICIPANTS: Patients with an ophthalmoscopically visible central ODP in either eye, irrespective of accompanying ocular disease, were enrolled from the neuro-ophthalmology and glaucoma referral practices. Each subject with a central ODP was matched with 2 healthy subjects with normal-appearing optic disc within 5 years of age. METHODS: Each participant received a complete ophthalmologic examination including standard automated perimetry, retinal nerve fiber layer (RNFL) thickness measurement by OCT, and serial horizontal and vertical cross-sectional EDI OCT of the optic nerve head. MAIN OUTCOME MEASURES: Structure of the lamina cribrosa (LC) in relation to the central ODP in EDI OCT images. RESULTS: Eighteen eyes (13 subjects) with a central ODP and 52 healthy eyes (26 controls) were included. Four eyes (2 subjects) with a central ODP were otherwise normal with intact macula, neuroretinal rim, RNFL, and visual field. Fourteen eyes (11 subjects) with a central ODP had glaucoma with glaucomatous neuroretinal rim thinning, RNFL loss, and corresponding visual field defect. No eye had associated maculopathy. On EDI OCT, the central ODP corresponded with a full-thickness defect in the LC center with no serous retinal detachment or herniation of neural tissue through the LC defect. Central ODPs were separated from (type 1) or merged with (type 2) the LC opening for the central retinal vascular trunk. In control eyes, no LC defect was detected. CONCLUSIONS: Central ODPs are full-thickness LC defects unassociated with maculopathy and different from glaucomatous acquired pits of the optic nerve, which represent focal laminar defect adjacent to the disc edge.

Enhanced depth imaging optical coherence tomography of optic nerve head drusen.

OBJECTIVE: To assess the value of enhanced depth imaging optical coherence tomography (EDI OCT) in diagnosing and evaluating optic nerve head drusen (ONHD) compared with conventional diagnostic methods. DESIGN: Prospective, comparative, cross-sectional study. PARTICIPANTS: Thirty-four patients with clinically visible or suspected ONHD in either eye based on dilated optic disc examination or optic disc stereophotography and without ocular comorbidity. METHODS: Spectral-domain OCT of the optic nerve head in both conventional (non-EDI) and EDI modes, ultrasound B-scan, and standard automated perimetry were performed on both eyes of all participants. MAIN OUTCOME MEASURES: Detection and findings of ONHD between EDI OCT and conventional diagnostic methods. RESULTS: Sixty-eight eyes were clinically classified into 3 groups: 32 eyes with definite ONHD, 25 eyes with suspected ONHD, and 11 normal-appearing fellow eyes. In the definite ONHD group, EDI OCT, non-EDI OCT, and ultrasound B-scan were positive for ONHD in all eyes and visual field (VF) was abnormal in 24 eyes. In the suspected ONHD group, EDI OCT, non-EDI OCT, ultrasound B-scan, and VF were positive in 17, 14, 7, and 3 eyes, respectively; 8 eyes had no evidence of ONHD in any of the tests. In normal-appearing fellow eyes, EDI OCT, non-EDI OCT, ultrasound B-scan, and VF were positive in 3, 1, 1, and 0 eyes, respectively; 4 eyes had no evidence of ONHD in any of the tests. Enhanced depth imaging OCT had a significantly higher ONHD detection rate than ultrasound B-scan in all eyes (52/68 eyes vs. 40/68 eyes; P<0.001), in eyes with clinically suspected ONHD or normal-appearing fellow eyes (20/36 eyes vs. 8/36 eyes; P<0.001), and in eyes with clinically suspected ONHD (17/25 eyes vs. 7/25 eyes; P = 0.002). Enhanced depth imaging OCT-detected ONHD appeared as signal-poor regions surrounded by short, hyper-reflective bands or isolated/clustered hyper-reflective bands without a signal-poor core. In non-EDI OCT, posterior surfaces of the ONHD and deep-seated hyper-reflective bands were invisible or less clear than in EDI OCT. CONCLUSIONS: Enhanced depth imaging OCT detects lesions likely representing ONHD more often and better assesses their shape and structure than conventional tests.

Prevalence of Chiari I malformation and cerebellar ectopia in patients with pseudotumor cerebri.

BACKGROUND: Chiari I malformation (CM) may be present pre-surgically in pseudotumor cerebri (PTC) patients. Whether inferior tonsillar displacement (ITD) is coincidental or linked to increased intracranial pressure is unclear. This study aimed to identify the prevalence of both CM and cerebellar ectopia (CE) (ITD below the foramen magnum > or = 5 mm and 2-4 mm, respectively) in PTC patients. METHODS: Retrospective review combined with prospective assessment of 68 PTC patients with available brain magnetic resonance imaging (MRI) scans and reports. Data collected included patient demographics, height, weight, co-morbid conditions, and medications. MRIs were analyzed for cerebellar tonsillar position, and results were compared with original reports. RESULTS: Of 68 PTC patients, 60 (88%) had normal position of the cerebellar tonsils and 8 (12%) had ITD by report. Of the latter group, 4 were identified as CM and 4 as CE. On review of MRIs, however, 16 patients (24%) had ITD, 7 having CM and 9 having CE. All patients with ITD were female, most were overweight or obese, and most had presumed idiopathic intracranial hypertension (IIH). CONCLUSION: ITD exists pre-surgically in a significant percentage of PTC patients. ITD is most common in obese or overweight women with presumed IIH. In fact, this subset of patients may actually represent a secondary form of PTC and may benefit from correction of ITD to restore normal intracranial pressure.

An unusual case of rhabdomyosarcoma presenting as orbital apex syndrome.

PRECIS: A 12-year-old female presented with symptoms and signs of orbital apex syndrome (OAS), secondary to stage IV alveolar rhabdomyosarcoma (RMS) originating in the sphenoid and ethmoid sinuses. OBJECTIVE: To present a case of alveolar rhabdomyosarcoma, unusual in its presentation as orbital apex syndrome and also its origin from the sphenoid and ethmoid sinuses. DESIGN: : Observational case report. METHODS: Ophthalmologic findings, neuroimaging, medical and surgical intervention, histopathologic analysis, and clinical course are described. RESULTS: A 12-year-old female presented with progressive visual loss in her left eye, difficulty with eye movements, and mild headache. Her examination was consistent with orbital apex syndrome. Imaging with contrast revealed a mass originating in the left sphenoid and ethmoid sinuses invading the left optic canal. Emergent biopsy was interpreted as alveolar rhabdomyosarcoma; subsequent metastatic work-up revealed bone marrow metastases. The patient was diagnosed with stage IV alveolar rhabdomyosarcoma and immediately started on combination orbital radiation therapy (RT) and systemic chemotherapy. She experienced gradual improvement of ocular motility, though her optic neuropathy persisted. CONCLUSION: Alveolar rhabdomyosarcoma of paranasal origin, specifically from the sphenoid and ethmoid sinuses, should be included in the differential diagnosis for orbital apex syndrome in children.

Intraocular injection of dibutyryl cyclic AMP promotes axon regeneration in rat optic nerve.

The optic nerve is a CNS pathway containing molecules capable of inhibiting axon elongation. The growth program in embryonic retinal ganglion cell (RGC) neurons enables axons to regenerate in the optic nerve through at least two mechanisms. Namely, high cyclic AMP (cAMP) levels abrogate the ability of CNS molecules to inhibit elongation, and the pattern of gene expression enables axons to undergo rapid, sustained, and lengthy elongation. In adult mammals, recovery of visual function after optic nerve injury is limited by both the death of most RGC neurons and the inability of surviving axons to regenerate. We now report that a single intraocular injection of the membrane-permeable cAMP analogue dibutyryl cAMP (db cAMP) promotes the regeneration of RGC axons in the optic nerves of adult rats, but does not prevent the death of RGC neurons. This regeneration in optic nerves crushed within the orbit (2 mm from the eye) was equally effective either 1 day before or 1 day after db cAMP injection. The number of regenerating axons, which was maximal 14 days after crush, declined with increasing time after injury (i.e., 28, 56, and 112 days) and distance beyond the crush site (i.e., 0.25, 0.5, and 1.0 mm). Thus, db cAMP promotes optic nerve regeneration without increasing the survival of axotomized RGC neurons. Furthermore, since db cAMP does not enable axons to undergo rapid, sustained, and lengthy elongation, strategies that increase survival and promote these changes in elongation may critically complement the ability of db cAMP to promote regeneration.

Chronic myokymia limited to the eyelid is a benign condition.

BACKGROUND: Eyelid myokymia, unlike myokymia of the other facial muscles, is assumed to be a benign, self-limited disorder. However, no systematic follow-up study has been performed on patients with chronic, isolated eyelid myokymia to verify its benign nature. METHODS: Retrospective single-institution chart review of 15 patients examined between 1983 and 2002 with a diagnosis of isolated eyelid myokymia who have had at least 12 months of follow-up. RESULTS: In all patients, symptoms began as unilateral, weekly or biweekly, intermittent eyelid spasms, and progressed to daily spasms over several months. The mean duration of symptoms at first examination was 91 months (range 2.5 months to 20 years). In no patient was the myokymia the first manifestation of a neurologic disease, although one patient progressed to ipsilateral hemifacial spasm. Thirteen patients (86.7%) underwent neuroimaging that gave negative results. The myokymia resolved spontaneously in four patients. Of the remaining 11 patients, eight were treated with botulinum toxin injection at regular intervals, with most reporting an improvement in symptoms. CONCLUSION: Chronic isolated eyelid myokymia is a benign condition. It tends not to progress to other facial movement disorders or to be associated with other neurologic disease. It responds well to treatment with botulinum toxin.