Teprotumumab in Clinical Practice: Recommendations and Considerations From the OPTIC Trial Investigators.

BACKGROUND: Thyroid eye disease (TED) is a vision-threatening and debilitating condition that until very recently had no Food and Drug Administration (FDA)-approved medical therapies. Teprotumumab has recently been approved to treat TED. We aim to provide guidance for its use, based on the input of the US investigators who participated in Phase 2 and Phase 3 clinical trials. METHODS: An expert panel was convened on October 11th and November 16th of 2019. All panel members had extensive experience as investigators in the Phase 2 and/or Phase 3 clinical trials of teprotumumab. Consensus among those investigators was reached to determine patient characteristics most appropriate for teprotumumab treatment. Safety guidelines were also reviewed and agreed on. RESULTS: The authors recommend that teprotumumab be considered first-line therapy for patients with clinically significant ophthalmopathy, including those with disease duration exceeding 9 months. The clinical activity score (CAS) may be useful for longitudinal monitoring but should not be used to determine treatment eligibility. Criteria will likely be expanded after more experience with the drug. Using teprotumumab for patients with TED with substantial signs, symptoms, or morbidity without a CAS score of >4 (e.g., progressive proptosis, diplopia, and early compressive optic neuropathy) or more, could be considered. Diabetes mellitus and inflammatory bowel disease comorbidities should not be exclusionary, but stringent monitoring in these patients is recommended. Drug dosing, administration interval, and duration should adhere to the study protocol: 8 infusions, separated by 3 weeks. Patients with more severe disease may benefit from additional doses. Corticosteroids can be used before or during teprotumumab therapy. Clinical and laboratory monitoring should be consistent with good clinical practice for patients receiving teprotumumab. CONCLUSIONS: Confirming the efficacy of teprotumumab usage outside the narrow parameters of the completed clinical trials will require rigorous scientific validation. As a step in that direction, we believe its on-label usage is appropriately applied to all patients with TED with substantial symptoms or morbidity, as judged by their physician.

Comparison of multifocal visual evoked potential, standard automated perimetry and optical coherence tomography in assessing visual pathway in multiple sclerosis patients.

BACKGROUND: Multifocal visual evoked potentials (mfVEP) measure local response amplitude and latency in the field of vision. OBJECTIVE: To compare the sensitivity of mfVEP, Humphrey visual field (HVF) and optical coherence tomography (OCT) in detecting visual abnormality in multiple sclerosis (MS) patients. METHODS: mfVEP, HVF, and OCT (retinal nerve fiber layer [RNFL]) were performed in 47 MS-ON eyes (last optic neuritis [ON] attack >or=6 months prior) and 65 MS-no-ON eyes without ON history. Criteria to define an eye as abnormal were: (1) mfVEP amplitude/latency - either amplitude or latency probability plots meeting cluster criteria with 95% specificity; (2) mfVEP amplitude or latency alone (specificity: 97% and 98%, respectively); and (3) HVF and OCT, mean deviation and RNFL thickness meeting p < 0.05, respectively. RESULTS: MfVEP (amplitude/latency) identified more abnormality in MS-ON eyes (89%) than HVF (72%), OCT (62%), mfVEP amplitude (66%) or latency (67%) alone. Eighteen percent of MS-no-ON eyes were abnormal for both mfVEP (amplitude/latency) and HVF compared with 8% with OCT. Agreement between tests ranged from 60% to 79%. mfVEP (amplitude/latency) categorized an additional 15% of MS-ON eyes as abnormal compared with HVF and OCT combined. CONCLUSIONS: mfVEP, which detects both demyelination (increased latency) and neural degeneration (reduced amplitude), revealed more abnormality than HVF or OCT in MS patients.

Neuro-ophthalmologic complications and manifestations of upper and lower motor neuron facial paresis.

The facial nerve (cranial nerve VII) courses a long pathway beginning in the precentral gyrus and ending at the facial muscles, lacrimal and salivary glands, and structures of the inner ear. Lesions along this pathway, clinically divided into upper and lower motor neuron lesions, present with unique characteristics that assist the physician in identifying the lesion site. The sequelae particularly of peripheral CN VII palsies, may result in significant and chronic damage to the cornea that may be challenging for the physician and patient.

Comparison of optical coherence tomography and scanning laser polarimetry measurements in patients with multiple sclerosis.

PURPOSE: To compare optical coherence tomography (OCT) and scanning laser polarimetry (GDx) measurements of the retinal nerve fiber layer (RNFL) in multiple sclerosis (MS) patients with and without optic neuritis (ON). METHODS: OCT and GDx were performed on 68 MS patients. Qualifying eyes were divided into two groups: 51 eyes with an ON history > or =6 months before (ON eyes) and 65 eyes with no history of ON (non-ON eyes). Several GDx and OCT parameters and criteria were used to define an eye as abnormal, for example, GDx nerve fiber indicator (NFI) >20 or 30, OCT average RNFL thickness, and GDx temporal-superior-nasal-inferior-temporal average (TSNIT) below 5 or 1% of the normative database of the instruments. Agreement between OCT and GDx parameters was reported as percent of observed agreement, along with the AC1 statistic. Linear regression analyses were used to examine the relationship between OCT average RNFL thickness and GDx NFI and TSNIT. RESULTS: All OCT and GDx measurements showed significantly more RNFL damage in ON than in non-ON eyes. Agreement between OCT and GDx parameters ranged from 69 to 90% (AC1 0.37 to 0.81) in ON eyes and 52 to 91% (AC1 = 0.21 to 0.90) in non-ON eyes. Best agreement was observed between OCT average RNFL thickness (p < 0.01) and NFI (>30) in ON eyes (90%, AC1 = 0.81) and between OCT average RNFL thickness (p < 0.01) and GDx TSNIT average (p < 0.01) in non-ON eyes (91%, AC1 = 0.90). In ON eyes, the OCT average RNFL thickness showed good linear correlation with NFI (R = 0.69, p < 0.0001) and TSNIT (R = 0.55, p < 0.0001). CONCLUSIONS: OCT and GDx show good agreement and can be useful in detecting RNFL loss in MS/ON eyes.

Cancer-associated retinopathy in neuroendocrine carcinoma of the fallopian tube.

A 70-year-old woman developed progressive visual loss with compromised visual acuity and visual fields, cells in the anterior chamber and vitreous, attenuated retinal arterioles, and macular edema. She had undergone right oophorectomy and partial salpingectomy nearly 50 years earlier. Full-field and multifocal electroretinography showed waveforms of markedly attenuated amplitudes, findings consistent with cancer-associated retinopathy (CAR). Positron emission tomography revealed a nodule in the anterior wall of a right hydrosalpinx. Total laparoscopic hysterectomy yielded a neuroendocrine fallopian tube malignancy. She underwent partial treatment with paclitaxel and carboplatin that was aborted because of the development of herpes zoster infection. At 15 months following diagnosis, her ophthalmic status was stable. This is the first report of CAR in neuroendocrine carcinoma of the fallopian tube.

Assessing visual pathway function in multiple sclerosis patients with multifocal visual evoked potentials.

Multifocal visual evoked potentials provide a topographic measure of visual response amplitude and latency. The objective of this study was to evaluate the sensitivity and specificity of the multifocal visual evoked potential technique in detecting visual abnormalities in patients with multiple sclerosis. Multifocal visual evoked potentials were recorded from 74 patients with multiple sclerosis with history of optic neuritis (MS-ON, n = 74 eyes) or without (MS-no-ON, n = 71 eyes), and 50 normal subjects (controls, n = 100 eyes) using a 60-sector pattern reversal dartboard stimulus (VERIS). Amplitude and latency for each sector were compared with normative data and assigned probabilities. Size and location of clusters of adjacent abnormal sectors (p < 0.05) were examined. Mean response amplitudes were (+/- SE) 0.39 +/- 0.02, 0.53 +/- 0.02, and 0.60 +/- 0.01 for MS-ON, MS-no-ON, and control groups, respectively, with significant differences between all groups (p < 0.0001). Mean latencies (ms; +/-SE relative to normative data) were 12.7 +/- 1.3 (MS-ON), 4.3 +/- 1.1 (MS-no-ON), and 0.3 +/- 0.4 (controls); group differences again significant (p < 0.0001). Half the MS-ON eyes had clusters larger than five sectors compared with 13% in MS-no-ON and 2% in controls. Abnormal sectors were distributed diffusely, although the largest cluster was smaller than 15 sectors in two-thirds of MS-ON eyes. Cluster criteria combining amplitude and latency showed an area of 0.96 under the receiver operating characteristic curve, yielding a criterion with 91% sensitivity and 95% specificity. We conclude that the multifocal visual evoked potential provides high sensitivity and specificity in detecting abnormalities in visual function in multiple sclerosis patients.

Retinal toxicity secondary to Plaquenil therapy.

BACKGROUND: Hydroxychloroquine sulfate (Plaquenil; Sanofi-Aventis, Bridgewater, New Jersey) is an antimalarial agent, which is sometimes used for the treatment of certain autoimmune disorders. Its use has been associated with ocular side effects; the most concerning is toxic maculopathy. CASE REPORT: A 71-year-old arthritic white woman requested a second opinion regarding retinal Plaquenil toxicity. The patients history was significant for seronegative rheumatoid arthritis diagnosed 6 years prior. She had taken Plaquenil 400 mg a day for about 5 years but had discontinued the drug 6 months before when bilateral central scotomas were first noted. At the consultation visit, her visual acuities were 20/20 in both eyes. SITA-Standard 10-2 disclosed a dense scotoma with 4 degrees of central sparing in each eye. Fundus examination found retinal pigment epithelium changes bilaterally; no "bulls eye" retinopathy was observed. CONCLUSION: Withdrawal of the medication is the only effective treatment for Plaquenil toxicity and, even then, the toxic effects may progress because of the slow clearance of the drug. Though controversy exists regarding screening recommendations, a baseline ophthalmic examination should be performed on all patients before initiating Plaquenil. If a patient is considered low risk, examinations can be scheduled annually. For high-risk patients, 6-month progress visits are strongly recommended.

Dynamic contrast-enhanced MRI of orbital and anterior visual pathway lesions.

PURPOSE: The accurate diagnosis of orbital and anterior visual pathway lesions has clinical significance. We determined whether dynamic contrast-enhanced MRI could differentiate benign from malignant lesions and compared model-independent and model-dependent methods of data analysis. METHODS: We retrospectively reviewed dynamic contrast-enhanced MRI studies of 37 enhancing orbital and anterior visual pathway lesions. The data were processed using model-independent analysis and model-dependent analysis using a 2-compartment pharmacokinetic model. The time-signal intensity curve and semiquantitative parameters from the model-independent method (area under the curve [AUC] after the initial 60, 90, and 120 s; time to peak; maximum signal enhancement ratio; maximum slope of increase; and washout ratio) and the quantitative parameters from the model-dependent method (Ktrans, kep, and ve) were derived for comparison with pathologic diagnoses. RESULTS: The time-signal intensity curves demonstrated different perfusion characteristics and were classified into 4 types. All the lesions that demonstrated curve types 1 and 4 were benign, while type 3 lesions were significantly associated with malignancy (P = 0.001). AUC60, AUC90, AUC120, and kep were significantly lower in benign lesions than in malignant lesions (P = 0.020, 0.018, 0.015, and 0.018, respectively). Receiver operating characteristic analysis indicated that AUC120 yielded the best diagnostic accuracy (area under the curve, 0.80; 95% CI, 0.64-0.96) in differentiating between benign and malignant lesions. CONCLUSIONS: Dynamic contrast-enhanced MRI is useful in evaluating orbital and anterior visual pathway lesions. The model-independent analysis method is equivalent to the model-dependent method in differentiating benign from malignant lesions.

The relationship between visual field and retinal nerve fiber layer measurements in patients with multiple sclerosis.

PURPOSE: To investigate the relationship between visual function, measured by standard automated perimetry (SAP), and retinal nerve fiber layer (RNFL) thickness, measured by optical coherence tomography (OCT), in patients with multiple sclerosis (MS). METHODS: SAP and RNFL thickness were measured in patients with MS in 28 eyes with the last optic neuritis (ON) >or=6 months prior (ON group) and 33 eyes without ON history (non-ON group). Abnormal overall or quadrant RNFL thickness was defined by measured values below 5% of the norm. A whole visual field or a sector of the field was classified as abnormal by using cluster criteria on total-deviation plots. Agreement between SAP and OCT results in classifying eyes/sectors was presented as a percentage of observed agreement, along with the AC1 statistic, which corrects for chance agreement. Regression analyses were performed relating several SAP parameters and RNFL thickness in the ON group. RESULTS: ON eyes showed more loss of visual sensitivity (MD, P = 0.02) and more loss of RNFL thickness (P < 0.0001) than did non-ON eyes. SAP and OCT agreed in 86% (AC1 = 0.78) of eyes and 69% (AC1 = 0.38) of sectors in the ON group and 61% (AC1 = 0.33) of eyes and 66% (AC1 = 0.48) of sectors in the non-ON group. Overall RNFL thickness was related to MD (dB) by a simple exponential function (R(2) = 0.48), supporting a linear relationship between these measures when both are expressed on linear scales. Absolute Pearson correlation coefficients for overall RNFL thickness and several SAP parameters ranged from 0.51 to 0.69. CONCLUSIONS: Good agreement between SAP and OCT was found in ON eyes but not in non-ON eyes or in individual sectors in either group. The findings in this study provide further support for the utility of combining structural and functional testing in clinical research on patients with MS, as well as in future neuroprotection trials for which the anterior visual pathways in patients with MS and optic neuritis may be used as a model.

Compressive optic neuropathy after use of oxidized regenerated cellulose in orbital surgery: review of complications, prophylaxis, and treatment.

PURPOSE: We report 2 cases of compressive optic neuropathy after use of oxidized regenerated cellulose (ORC) in orbital surgery. To our knowledge, no complications have been reported previously after use of this material in orbital surgery. We also review the complications related to its retention at operative sites outside the orbit and recommend precautions to avoid them. DESIGN: Retrospective interventional case reports. PARTICIPANTS: Two patients with compressive optic neuropathy after use of ORC in orbital surgery. METHODS: Case reports from 2 different clinics and review of the English scientific literature. MAIN OUTCOME MEASURES: Best-corrected visual acuity, extraocular motility, proptosis, and chemosis. RESULTS: One patient underwent orbital exploration and biopsy of an orbital tumor, and the second had repair of an orbital floor fracture. Postoperatively, both presented with chemosis, ophthalmoplegia, and progressive loss of vision. Orbital imaging revealed a retrobulbar soft-tissue density compatible with hematoma. Repeat orbital exploration revealed the soft-tissue mass to be swollen ORC. CONCLUSIONS: Retained intraorbital ORC may cause a compartment syndrome and should be suspected in postoperative patients with orbital symptoms. When ORC is used around the optic nerve, it should be removed after hemostasis is achieved.

Her vision was tied down.

A 50-year-old female presented with progressive painless vision loss in the left eye and was subsequently diagnosed to have a pituitary macroadenoma, consistent with a prolactinoma, which was compressing the chiasm primarily on the left and involving the left cavernous sinus. She was treated with oral bromocriptine, resulting in marked shrinkage of the tumor and significant visual field recovery. Subsequently, she again began noting progressive vision loss in both eyes and was initially thought to have pituitary tumor regrowth. Repeat brain MRI, however, showed chiasmal prolapse with inferior tethering into an empty sella. Surgical fat padding to reposition the chiasm resulted in visual improvement with a different visual field pattern in the left eye. The clinical manifestations and etiopathogenesis of the empty sella syndrome are discussed.

Telemedicine for eye care.

Tele-ophthalmology has been employed mainly for patients in under-served rural areas in need of specialty care, but other applications such as telementoring have also been used. In certain populations, cost containment is a significant issue and telemedicine is a solution. Tele-ophthalmology can be performed in realtime, by store-and-forward mode, or by hybrid techniques. After appropriate modification, a range of peripherals may be used for tele-ophthalmology, including the direct ophthalmoscope, indirect ophthalmoscope, slit lamp or retinal camera. Tele-ophthalmology applications include: detecting, screening and diagnosing diabetic retinopathy; anterior segment imaging; glaucoma screening; low vision consultation; telementoring. Tele-ophthalmology shows great promise for improving patient care and increasing access to specialty care not available in under-served areas. In developing countries tele-ophthalmology may be a cost-effective method by which richer countries can assist them.

Diagnostic Ophthalmic Ultrasound for Radiologists.

Ophthalmic ultrasound is an invaluable tool that provides quick and noninvasive evaluation of the eye and the orbit. It not only allows the clinicians to view structures that may not be visible with routine ophthalmic equipment or neuroimaging techniques but also provides unique diagnostic information in various ophthalmic conditions. In this article, the basic principles of ophthalmic ultrasound and examination techniques are discussed. Its clinical application is illustrated through a variety of ocular pathologic abnormalities (eg, narrow angles, ciliary body tumor, detached retina, choroidal melanoma, and papilledema).

Optical Coherence Tomography for the Radiologist.

Optical coherence tomography is an imaging technique using low coherence light sources to produce high-resolution cross-sectional images. This article reviews pertinent anatomy and various pathologies causing optic atrophy (eg, compressive, infiltrating, demyelinating) versus optic nerve swelling (from increased intracranial pressure known as papilledema or other optic nerve intrinsic pathologies). On optical coherence tomography, optic atrophy is often associated with reduced average retinal nerve fiber layer thickness, whereas optic nerve swelling is usually associated with increased average retinal nerve fiber layer thickness.

Photopic ERGs in patients with optic neuropathies: comparison with primate ERGs after pharmacologic blockade of inner retina.

PURPOSE: To determine whether anterior ischemic optic neuropathy and compressive optic neuropathy in humans alter the photopic flash ERG and to investigate the cellular origins of the waves that are affected by pharmacologic agents in primates. METHODS: Photopic flash ERGs were recorded differentially, with DTL electrodes, between the two eyes of 22 patients with diagnosed optic neuropathy (n = 17, anterior ischemic optic neuropathy [AION]; n = 5, compressive optic neuropathy) and 25 age-matched control subjects and in 17 eyes of 13 monkeys (Macaca mulatta). The stimulus consisted of brief (<5 ms) red (lambda(max) = 660 nm) Ganzfeld flashes (energy range, 0.5-2.0 log td-s) delivered on a rod-saturating blue background of 3.7 log sc td (lambda(max) = 460 nm). An eye of the patient with ischemic changes at the disc was classified as symptomatic if it showed visual field defects with a mean deviation (MD) of P < 2%. Recordings in macaque monkeys were made before and after inner retinal blockade with tetrodotoxin (TTX) (1.2-2.1 microM; n = 7), TTX+N-methyl-d-aspartate (NMDA; 1.4-6.4 mM; n = 7), and cis-2, 3 piperidine dicarboxylic acid (PDA; 3.3-3.8 mM; n = 3). RESULTS: The PhNR amplitude was significantly reduced in both symptomatic (P = 3.4 x 10(-8)) and asymptomatic (P = 0.036) eyes of patients with AION or compressive optic neuropathy (P = 0.0054) compared with control subjects. The PhNR amplitude in the symptomatic eye showed a moderate correlation with field defects (P < 0.05) similar to previous findings in open-angle glaucoma. The a-wave also was reduced significantly in the symptomatic eye (P = 0.0002) of patients with AION. The i-wave, a positive wave on the trailing edge of the b-wave peaking around 50 ms, became more prominent in eyes in which the PhNR was significantly reduced. In monkeys, the PhNR was eliminated by TTX. The a-wave at the peak and later times was reduced by TTX, further reduced by NMDA, and eliminated after PDA in response to the red stimuli. PDA also eliminated the i-wave. CONCLUSIONS: PhNR amplitude is significantly reduced in eyes with open-angle glaucoma, AION, and compressive optic neuropathy. Experiments in primates indicate that this reduction reflects loss of a spike-driven contribution to the photopic ERG. There also are small spike-driven contributions to the a-wave elicited by full-field red stimuli. The i-wave, which becomes more prominent when the PhNR is reduced, has origins in the off-pathway distal to the ganglion cells.

Superior ophthalmic vein thrombosis in a patient with chronic myeloid leukemia receiving antifibrinolytic and thrombopoietin receptor agonist therapy.

Isolated superior ophthalmic vein (SOV) thrombosis is a rare condition usually related to inflammation of the orbit or paranasal sinuses. Patients present with acute orbital signs, including proptosis, ophthalmoplegia, globe dystopia, and periorbital edema, and may have diminished vision secondary to optic neuropathy. SOV thrombosis is typically seen in the setting of septic cavernous sinus thrombosis, and antimicrobial therapy is the treatment of choice. We herein report what may be the first case of isolated SOV thrombosis related to hypercoagulability in a patient with cancer who was receiving antifibrinolytic and thrombopoietin receptor agonist medications.

Spectrum of pediatric neuromyelitis optica.

OBJECTIVE: Our goal was to describe the spectrum of clinical phenotypes, laboratory and imaging features, and treatment in pediatric patients with neuromyelitis optica. PATIENTS AND METHODS: The study consisted of a retrospective chart review of patients followed in a pediatric multiple sclerosis center with a diagnosis of neuromyelitis optica spectrum disorder. RESULTS: Nine patients with neuromyelitis optica spectrum disorders were included, all of whom were female. There were 4 black children, 2 Latin American children, 2 white children, and 1 child of mixed Latin American/white heritage. Median age at initial attack was 14 years (range: 1.9-16 years). Median disease duration was 4 years (range: 0.6-9 years). Tests for neuromyelitis optica immunoglobulin G were positive for 7 patients. Eight patients had transverse myelitis and optic neuritis, and 1 patient had longitudinally extensive transverse myelitis without optic neuritis but had a positive neuromyelitis optica immunoglobulin G antibody titer. Cerebral involvement on MRI was found in all subjects, 5 of whom were symptomatic with encephalopathy, seizures, hemiparesis, aphasia, vomiting, or hiccups. Immunosuppressive therapy reduced attack frequency and progression of disability. CONCLUSIONS: Pediatric neuromyelitis optica has a diverse clinical presentation and may be difficult to distinguish from multiple sclerosis in the early stages of the disease. The recognition of the broad spectrum of this disease to include signs and symptoms of brain involvement is aided by the availability of a serum biomarker: neuromyelitis optica immunoglobulin G. Early diagnosis and immunosuppresive treatment may help to slow the accumulation of severe disability.

Evaluation and treatment of papilledema in pregnancy.

Papilledema is defined as optic disk edema that is secondary to increased intracranial pressure. During pregnancy, papilledema poses additional diagnostic and therapeutic challenges. As in the nonpregnant patient, the primary goal is to urgently determine the cause of the papilledema followed by implementing appropriate management for life-threatening conditions in a timely fashion while safeguarding the fetus. Papilledema may occur also in conditions that are not life threatening; in either case, papilledema may cause visual failure. We describe the two most common causes of papilledema during pregnancy, idiopathic intracranial hypertension and cerebral venous thrombosis. In the former, there is no threat to life, while in the latter, depending on the extent of the cerebral venous thrombosis, life-threatening medical issues may dominate the picture. In these conditions, attention to the prevention of visual failure is of major importance; however, treatment options may need to be modified to safeguard the developing fetus. In this article, we review the current diagnostic and treatment options for patients with papilledema, emphasizing special considerations for the pregnant patient, including a chart to help the clinician differentiate between the different conditions causing papilledema. A flow chart suggests an approach as to how to monitor vision function and steps to take to prevent visual loss in these conditions causing papilledema. Drugs that may be considered in the management of papilledema are reviewed, and the FDA information regarding their safety for the fetus is provided.

Medical and surgical management of idiopathic intracranial hypertension in pregnancy.

Idiopathic intracranial hypertension (IIH) is a syndrome of increased intracranial pressure without hydrocephalus or mass lesion with elevated cerebrospinal fluid (CSF) pressure but otherwise normal CSF composition. It has been found that pregnancy occurs in IIH patients at about the same rate as in the general population, that IIH can occur in any trimester of pregnancy, that patients have the same spontaneous abortion rate as the general population, and that the visual outcome is the same as for nonpregnant patients with IIH. Although it is also stated that pregnant patients with IIH should be managed and treated the same way as any other patient with IIH, the use of imaging and drug contraindications do make a difference between the two groups. The treatment has two major goals, which are to preserve vision and to improve symptoms. The medical therapy includes weight control, nonketotic diet, serial lumbar punctures, diuretics, steroids, and certain analgesics. When medical therapy fails, surgical procedures should be considered. The two main procedures are optic nerve sheath fenestration and lumboperitoneal shunt. Anesthetic considerations in the pregnant patient are an additional factor when surgeries are contemplated. It is also noted that therapeutic abortion to limit progression of disease is not indicated and that subsequent pregnancies do not increase the risk of recurrence.