Efficacy and Safety of Teprotumumab in Patients With Thyroid Eye Disease of Long Duration and Low Disease Activity.

CONTEXT: Early inflammatory thyroid eye disease (TED) can lead to symptomatic chronic disease, including disabling proptosis. Teprotumumab, an insulin-like growth factor-1 receptor (IGF-1R) inhibitor, previously demonstrated efficacy in acute, high-inflammation TED trials. OBJECTIVE: We present data from the first placebo-controlled trial with teprotumumab in chronic/low disease activity TED. METHODS: This randomized double-masked, placebo-controlled trial, conducted at 11 US centers, enrolled adult participants with TED duration of 2 to 10 years, Clinical Activity Score (CAS) ≤ 1 or no additional inflammation or progression in proptosis/diplopia for ≥1 year, proptosis ≥3 mm from before TED and/or from normal, euthyroid/mildly hypo/hyperthyroid, no prior teprotumumab, and no steroids within 3 weeks of baseline. Patients received (2:1) intravenous teprotumumab or placebo once every 3 weeks (total 8 infusions). The primary endpoint was proptosis (mm) improvement at Week 24. Adverse events (AEs) were assessed. RESULTS: A total of 62 (42 teprotumumab and 20 placebo) patients were randomized. At Week 24, least squares mean (SE) proptosis improvement was greater with teprotumumab (-2.41 [0.228]) than with placebo (-0.92 [0.323]), difference -1.48 (95% CI -2.28, -0.69; P = .0004). Proportions of patients with AEs were similar between groups. Hyperglycemia was reported in 6 (15%) vs 2 (10%) and hearing impairment in 9 (22%) vs 2 (10%) with teprotumumab and placebo, respectively. AEs led to discontinuation in 1 teprotumumab (left ear conductive hearing loss with congenital anomaly) and 1 placebo patient (infusion-related). There were no deaths. CONCLUSION: Teprotumumab significantly improved proptosis vs placebo in longstanding/low inflammation TED, demonstrating efficacy regardless of disease duration/activity. The safety profile was comparable to that previously reported.

Primary balloon angioplasty of venous Sinus stenosis in idiopathic intracranial hypertension.

BACKGROUND: Venous sinus stenosis (VSS) stenting has emerged as an effective treatment for patients with Idiopathic Intracranial Hypertension (IIH). However, stenting carries risk of in-stent stenosis/thrombosis and cumulative bleeding risk from long-term dual antiplatelet (DAPT) use. Thus, we investigated the potential safety and efficacy of primary balloon angioplasty as an alternative to stenting in IIH. METHODS: A prospectively maintained single-center registry of IIH patients undergoing endovascular procedures was queried. Inclusion criteria included patients with confirmed IIH and angiographically demonstrable VSS who underwent interventions from 2012- 2021. Patients were dichotomized into primary balloon angioplasty (Group A) and primary stenting (Group S), comparing clinical outcomes using bivariate analyses. RESULTS: 62 patients were included with median age of 33 [IQR 26-37], 74% females. Group A (9/62) and Group S (53/62) had similar baseline characteristics. Papilledema improvement was higher in Group S at 6 weeks and 6 months (44 vs. 93, p = 0.002 and 44 vs. 92%, p = 0.004), with similar improvements across all symptoms. Group S had higher mean post-procedure venous pressure gradient change (8 vs. 3 mmHg, p = 0.02) and a lower CSF opening pressure at 6 months (23 vs. 36 cmH2O, p < 0.001). VPS rescue rate was higher in Group A (44 vs. 2%, p = 0.001). There was only one procedural complications; a subdural hematoma in Group A. CONCLUSIONS: Primary VSS balloon angioplasty provides a marginal and short-lived improvement of IIH symptoms compared to stenting. These findings suggest a cautious and limited role for short-term rescue angioplasty in poor shunting and stenting candidates with refractory IIH.

Venous Sinus Stenting for Low Pressure Gradient Stenoses in Idiopathic Intracranial Hypertension.

BACKGROUND: Medically refractory idiopathic intracranial hypertension (IIH) is frequently treated with venous sinus stenosis stenting with high success rates. Patient selection has been driven almost exclusively by identification of supraphysiological venous pressure gradients across stenotic regions based on theoretical assessment of likelihood of response. OBJECTIVE: To explore the possibility of benefit in low venous pressure gradient patients. METHODS: Using a single-center, prospectively maintained registry of patients with IIH undergoing venous stenting, we defined treatment groups by gradient pressures of ≤4, 5 to 8, and >8 mmHg based on the most frequently previously published thresholds for stenting. Baseline demographics, clinical, and neuro-ophthalmological outcomes (including optical coherence tomography and Humphrey visual fields) were compared. RESULTS: Among 53 patients, the mean age was 32 years and 70% female with a mean body mass index was 36 kg/m 2 . Baseline characteristics were similar between groups. The mean change in lumbar puncture opening pressure at 6 months poststenting was similar between the 3 groups (≤4, 5-8, and >8 mmHg; 13.4, 12.9, and 12.4 cmH 2 O, P = .47). Papilledema improvement was observed across groups at 6 months (100, 93, and 86, P = .7) as were all clinical symptoms. The mean changes in optical coherence tomography retinal nerve fiber layer (-30, -54, and -104, P = .5) and mean deviation in Humphrey visual fields (60, 64, and 67, P = .5) at 6 weeks were not significantly different. CONCLUSION: Patients with IH with low venous pressure gradient venous sinus stenosis seem to benefit equally from venous stenting compared with their higher gradient counterparts. Re-evaluation of our restrictive criteria for this potentially vision sparing intervention is warranted. Future prospective confirmatory studies are needed.

Thyroid dermopathy responds to teprotumumab therapy.

Summary: Thyroid dermopathy is an uncommon manifestation of thyroid disease that impairs the quality of life in certain cases. Currently, the available treatments offer limited results and a chance of recurrence. Teprotumumab, a novel medication that results in the regression of thyroid ophthalmopathy, may have similar effects on dermopathy. We describe four patients treated with teprotumumab for their thyroid ophthalmopathy who concomitantly had dermatopathy upon initiation of their infusions. Patients improved after two to three infusions and three out of the four patients have not suffered a recurrence.Teprotumumab is a monoclonal antibody (MAB) that attenuates an inflammatory response, resulting in decreased edema and tissue expansion. Given the similarities of their pathophysiology, we believe that the resolution of thyroid dermatopathy and regression of thyroid eye disease occurs via the same mechanism. We encourage further investigation utilizing teprotumumab for patients whose dermopathy is associated with impaired quality of life. Learning points: Thyroid dermopathy (TD), an uncommon manifestation of thyroid disease, may occasionally impair function and quality of life. There are only a few treatments for TD, with limited results and high rates of recurrence. Teprotumumab is a Food and Drug Administration-approved medication used for thyroid eye disease (TED). Our patients treated with teprotumumab for TED showed improvement of TD, which demonstrates its potential use for this condition.

Teprotumumab Efficacy, Safety, and Durability in Longer-Duration Thyroid Eye Disease and Re-treatment: OPTIC-X Study.

PURPOSE: To evaluate teprotumumab safety/efficacy in patients with thyroid eye disease (TED) who were nonresponsive or who experienced a disease flare. DESIGN: The Treatment of Graves' Orbitopathy to Reduce Proptosis with Teprotumumab Infusions in an Open-Label Clinical Extension Study (OPTIC-X) is a teprotumumab treatment and re-treatment trial following the placebo-controlled teprotumumab Phase 3 Treatment of Graves' Orbitopathy (Thyroid Eye Disease) to Reduce Proptosis with Teprotumumab Infusions in a Randomized, Placebo-Controlled, Clinical Study (OPTIC) trial. PARTICIPANTS: Patients who previously received placebo (n = 37) or teprotumumab (n = 14) in OPTIC. METHODS: OPTIC nonresponders or those who flared (≥2-mm increase in proptosis, ≥2-point increase in clinical activity score [CAS], or both) during follow-up were treated for the first time (previous placebo patients) or re-treated with teprotumumab in OPTIC-X with 8 infusions over 24 weeks. MAIN OUTCOME MEASURES: Proptosis response and safety. Secondary outcomes included proptosis, CAS, subjective diplopia, and quality-of-life. RESULTS: Thirty-three of 37 placebo-treated OPTIC patients (89.2%) became proptosis responders (mean ± standard deviation, -3.5 ± 1.7 mm) when treated with teprotumumab in OPTIC-X. The responses were equivalent to the OPTIC study. In these responders, proptosis, CAS of 0 or 1, and diplopia responses were maintained in 29 of 32 patients (90.6%), 20 of 21 patients (95.2%), and 12 of 14 patients (85.7%), respectively, at follow-up week 48. The median TED duration was 12.9 months versus 6.3 months in those treated with teprotumumab in the OPTIC study. Of the 5 OPTIC teprotumumab nonresponders re-treated in OPTIC-X, 2 responded, 1 showed a proptosis reduction of 1.5 mm from OPTIC baseline, and 2 discontinued treatment early. Of the OPTIC teprotumumab responders who experienced flare, 5 of 8 patients (62.5%) responded when re-treated (mean proptosis reduction, 1.9 ± 1.2 mm from OPTIC-X baseline and 3.3 ± 0.7 mm from OPTIC baseline). Compared with published double-masked trials and their integrated follow-up, no new safety signals were identified. Mild hearing impairment was reported; 4 events occurred during the first course of treatment, and 2 events reoccurred after re-treatment. CONCLUSIONS: Patients with TED of longer disease duration responded similarly to those treated earlier in the disease course. Patients with an insufficient initial response or flare may benefit from additional teprotumumab therapy. No new safety risk was identified; however additional postmarketing pharmacovigilance is ongoing.

Neuroimaging Features of Intracranial Hypertension in Pediatric Patients With New-Onset Idiopathic Seizures, a Comparison With Patients with Confirmed Diagnosis of Idiopathic Intracranial Hypertension: A Preliminary Study.

CONCLUSION: A cutoff value of 6.0 mm for optic nerve sheath dilation may be used as a screening imaging marker to suspect elevated opening pressure with specificity of 88% in pediatric patients with new-onset idiopathic seizures.

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.

Teprotumumab for the Treatment of Active Thyroid Eye Disease.

BACKGROUND: Thyroid eye disease is a debilitating, disfiguring, and potentially blinding periocular condition for which no Food and Drug Administration-approved medical therapy is available. Strong evidence has implicated the insulin-like growth factor I receptor (IGF-IR) in the pathogenesis of this disease. METHODS: In a randomized, double-masked, placebo-controlled, phase 3 multicenter trial, we assigned patients with active thyroid eye disease in a 1:1 ratio to receive intravenous infusions of the IGF-IR inhibitor teprotumumab (10 mg per kilogram of body weight for the first infusion and 20 mg per kilogram for subsequent infusions) or placebo once every 3 weeks for 21 weeks; the last trial visit for this analysis was at week 24. The primary outcome was a proptosis response (a reduction in proptosis of ≥2 mm) at week 24. Prespecified secondary outcomes at week 24 were an overall response (a reduction of ≥2 points in the Clinical Activity Score plus a reduction in proptosis of ≥2 mm), a Clinical Activity Score of 0 or 1 (indicating no or minimal inflammation), the mean change in proptosis across trial visits (from baseline through week 24), a diplopia response (a reduction in diplopia of ≥1 grade), and the mean change in overall score on the Graves' ophthalmopathy-specific quality-of-life (GO-QOL) questionnaire across trial visits (from baseline through week 24; a mean change of ≥6 points is considered clinically meaningful). RESULTS: A total of 41 patients were assigned to the teprotumumab group and 42 to the placebo group. At week 24, the percentage of patients with a proptosis response was higher with teprotumumab than with placebo (83% [34 patients] vs. 10% [4 patients], P<0.001), with a number needed to treat of 1.36. All secondary outcomes were significantly better with teprotumumab than with placebo, including overall response (78% of patients [32] vs. 7% [3]), Clinical Activity Score of 0 or 1 (59% [24] vs. 21% [9]), the mean change in proptosis (-2.82 mm vs. -0.54 mm), diplopia response (68% [19 of 28] vs. 29% [8 of 28]), and the mean change in GO-QOL overall score (13.79 points vs. 4.43 points) (P≤0.001 for all). Reductions in extraocular muscle, orbital fat volume, or both were observed in 6 patients in the teprotumumab group who underwent orbital imaging. Most adverse events were mild or moderate in severity; two serious events occurred in the teprotumumab group, of which one (an infusion reaction) led to treatment discontinuation. CONCLUSIONS: Among patients with active thyroid eye disease, teprotumumab resulted in better outcomes with respect to proptosis, Clinical Activity Score, diplopia, and quality of life than placebo; serious adverse events were uncommon. (Funded by Horizon Therapeutics; OPTIC ClinicalTrials.gov number, NCT03298867, and EudraCT number, 2017-002763-18.).

Custom Optical Coherence Tomography Parameters for Distinguishing Papilledema from Pseudopapilledema.

SIGNIFICANCE: Causes of papilledema can be life-threatening; however, distinguishing papilledema from pseudopapilledema is often challenging. The conventional optical coherence tomography (OCT) scan for assessing the optic nerve often fails to detect mild papilledema. Our study suggests that parameters derived from volumetric OCT scans can provide additional useful information for detecting papilledema. PURPOSE: Optical coherence tomography analysis of the optic nerve commonly measures retinal nerve fiber layer thickness (RNFLT) along a 1.73-mm-radius scan path. This conventional scan, however, often fails to detect mild papilledema. The purpose of this study was to evaluate additional OCT-derived measures of the optic nerve head (ONH) and peripapillary retina for differentiating papilledema (all grades and mild) from pseudopapilledema. METHODS: Cirrus OCT ONH volume scans were acquired from 21 papilledema (15 mild papilledema), 27 pseudopapilledema, and 42 control subjects. Raw scan data were exported, and total retinal thickness within Bruch's membrane opening (BMO) plus RNFLT and total retinal thickness at the following eccentricities were calculated using custom algorithms: BMO to 250, 250 to 500, 500 to 1000, and 1000 to 1500 µm. Minimum rim width was calculated, and BMO height was measured from a 4-mm Bruch's membrane reference plane centered on the BMO. RESULTS: Retinal nerve fiber layer thickness from BMO to 250 µm, minimum rim width, and BMO height had significantly greater areas under the receiver operating characteristic curve than did conventional RNFLT for differentiating mild papilledema from pseudopapilledema (P < .0001) and greater sensitivities at 95% specificity. Using cutoff values at 95% specificity, custom parameters detected 10 mild papilledema patients, and conventional RNFLT detected only 1. Bruch's membrane opening heights above the reference plane were observed in papilledema only, although many papilledema cases had a neutral or negative BMO height. CONCLUSIONS: Using OCT volumetric data, additional parameters describing peripapillary tissue thickness, neuroretinal rim thickness, and ONH position can be calculated and provide valuable measures for differentiating mild papilledema from pseudopapilledema.

Multifocal visual evoked potentials and contrast sensitivity correlate with ganglion cell-inner plexiform layer thickness in multiple sclerosis.

OBJECTIVE: To examine the relationship between optical coherence tomography (OCT) macular ganglion cell-inner plexiform layer thickness (GCIPLT), peripapillary retinal nerve fiber layer thickness (RNFLT) and visual function in relapsing-remitting multiple sclerosis (RRMS). METHODS: Cirrus OCT, VERIS 60-sector multifocal visual evoked potential (mfVEP) and Pelli-Robson contrast sensitivity (CS) were obtained for 53 eyes with last optic neuritis (ON) > 6 months and 105 non-ON eyes in 90 patients. One eye (43 ON, 73 non-ON) was used for correlations when both had the same history. Global (G, 60 sectors) and central 5.6° (C, 24 sectors) mfVEP amplitude and latency were calculated as mean logSNR and median latency. RESULTS: Eyes showing abnormal mfVEP (amplitude or latency) vs OCT (GCIPLT or RNFLT) was 77% vs 69% (p = 0.33) in ON, 45% vs 22% (p < 0.0005) in non-ON. In ON and non-ON, mfVEP measures and CS correlated with GCIPLT and RNFLT (r = -0.24 to 0.78, p = 0.03-0.0001). In ON, mfVEP amplitude (C,G) correlated better with GCIPLT (r = 0.78, 0.76) than RNFLT (r = 0.43, 0.58; p < 0.001, 0.01). CONCLUSIONS: MfVEP measures and CS correlated well with GCIPLT and RNFLT in ON and non-ON. MfVEP amplitudes were more highly correlated with GCIPLT than RNFLT in ON. MfVEP detected significantly more defects than OCT in non-ON. SIGNIFICANCE: GCIPLT, mfVEP and CS provide useful measures of optic nerve integrity in RRMS.

Use of A-scan Ultrasound and Optical Coherence Tomography to Differentiate Papilledema From Pseudopapilledema.

SIGNIFICANCE: Differentiating papilledema from pseudopapilledema reflecting tilted/crowded optic discs or disc drusen is critical but can be challenging. Our study suggests that spectral-domain optical coherence tomography (OCT) peripapillary retinal nerve fiber layer thickness and retrobulbar optic nerve sheath diameter (ONSD) measured by A-scan ultrasound provide useful information when differentiating the two conditions. PURPOSE: To evaluate the use of A-scan ultrasound and spectral-domain OCT retinal nerve fiber layer thickness (RNFLT) in differentiating papilledema associated with idiopathic intracranial hypertension from pseudopapilledema. METHODS: Retrospective cross-sectional analysis included 23 papilledema and 28 pseudopapilledema patients. Ultrasound-measured ONSD at primary gaze, percent change in ONSD at lateral gaze (30° test), and peripapillary RNFLT were analyzed. Receiver operating characteristic curves were constructed using one eye from each subject. RESULTS: Compared with pseudopapilledema, papilledema eyes showed larger mean ONSD (5.4 ± 0.6 vs. 4.0 ± 0.3 mm, P < .0001), greater change of ONSD at lateral gaze (22.4 ± 8.4% vs. 2.8 ± 4.8%, P < .0001), and thicker retinal nerve fiber layer (219.1 ± 104.6 vs. 102.4 ± 20.1 µm, P < .0001). Optic nerve sheath diameter and 30° test had the greatest area under the receiver operating characteristic curve, 0.98 and 0.97, respectively; followed by inferior quadrant (0.90) and average RNFLT (0.87). All papilledema eyes with Frisén scale greater than grade II were accurately diagnosed by ONSD, 30° test, or OCT. In mild papilledema (Frisén scale grades I and II, n = 15), area under the receiver operating characteristic curve remained high for ONSD (0.95) and 30° test (0.93) but decreased to 0.61 to 0.71 for RNFLT. At 95% specificity, sensitivities for ONSD, 30° test, and RNFLT were 91.3%, 91.3%, and 56.5%, respectively, for the entire papilledema group and 80.0%, 86.7%, and 13.3% for the mild papilledema subgroup. CONCLUSIONS: Retinal nerve fiber layer thickness can potentially be used to detect moderate to severe papilledema. A-scan may further assist differentiation of mild papilledema from pseudopapilledema.

Teprotumumab for Thyroid-Associated Ophthalmopathy.

BACKGROUND: Thyroid-associated ophthalmopathy, a condition commonly associated with Graves' disease, remains inadequately treated. Current medical therapies, which primarily consist of glucocorticoids, have limited efficacy and present safety concerns. Inhibition of the insulin-like growth factor I receptor (IGF-IR) is a new therapeutic strategy to attenuate the underlying autoimmune pathogenesis of ophthalmopathy. METHODS: We conducted a multicenter, double-masked, randomized, placebo-controlled trial to determine the efficacy and safety of teprotumumab, a human monoclonal antibody inhibitor of IGF-IR, in patients with active, moderate-to-severe ophthalmopathy. A total of 88 patients were randomly assigned to receive placebo or active drug administered intravenously once every 3 weeks for a total of eight infusions. The primary end point was the response in the study eye. This response was defined as a reduction of 2 points or more in the Clinical Activity Score (scores range from 0 to 7, with a score of ≥3 indicating active thyroid-associated ophthalmopathy) and a reduction of 2 mm or more in proptosis at week 24. Secondary end points, measured as continuous variables, included proptosis, the Clinical Activity Score, and results on the Graves' ophthalmopathy-specific quality-of-life questionnaire. Adverse events were assessed. RESULTS: In the intention-to-treat population, 29 of 42 patients who received teprotumumab (69%), as compared with 9 of 45 patients who received placebo (20%), had a response at week 24 (P<0.001). Therapeutic effects were rapid; at week 6, a total of 18 of 42 patients in the teprotumumab group (43%) and 2 of 45 patients in the placebo group (4%) had a response (P<0.001). Differences between the groups increased at subsequent time points. The only drug-related adverse event was hyperglycemia in patients with diabetes; this event was controlled by adjusting medication for diabetes. CONCLUSIONS: In patients with active ophthalmopathy, teprotumumab was more effective than placebo in reducing proptosis and the Clinical Activity Score. (Funded by River Vision Development and others; ClinicalTrials.gov number, NCT01868997 .).

Surgical Resection of an Optic Nerve Sheath Meningioma: Relevance of Endoscopic Endonasal Approaches to the Optic Canal.

Optic nerve sheath meningiomas (ONSMs) account for less than 2% of meningiomas and 1.7% of orbital tumors. Although rare, the management of these tumors is important as unilateral blindness often results in untreated cases. Radiotherapy has emerged as the preferred treatment. However, therapies for ONSMs are controversial due to the variable natural history of the disease and limitations of surgical and radiotherapy options. A 60-year-old woman presented with monocular left diminished color perception and blurred vision. Magnetic resonance imaging demonstrated a homogenously enhancing 5-mm left optic nerve mass with evidence of nerve compression. Conservative management was advised. However, 1 month after diagnosis her visual acuity deteriorated further. Because of the small focal location of the tumor within the optic canal, surgery was considered. Given the tumor's location inferomedial to the optic nerve, an endoscopic endonasal approach to the optic canal was performed. This patient recovered fully with resolution of visual symptoms immediately following surgery. Postoperative imaging 24 hours after surgery demonstrated gross total resection of the tumor; 1 year postoperatively the patient has a normal ophthalmologic examination. This report highlights the value of endoscopic endonasal approaches in the management of select optic canal pathology, otherwise inaccessible via transcranial approaches.

Optical coherence tomography of the optic nerve head detects acute changes in intracranial pressure.

We aimed to determine if there are measurable objective changes in the optic nerve head (ONH) immediately after cerebrospinal fluid (CSF) drainage in a prospective case-series of five patients undergoing a clinically indicated lumbar puncture (LP) for diagnosis of idiopathic intracranial hypertension. A Cirrus high-definition optical coherence tomography machine (Carl Zeiss Meditec, Dublin, CA, USA) was used to acquire images in the lateral decubitus position. Optic disc cube and high-definition line raster scans centered on the ONH were obtained immediately before and after draining CSF, while the patient maintained the lateral decubitus position. Measured parameters included retinal nerve fiber layer (RNFL) thickness, peripapillary retinal pigment epithelium/Bruch's membrane (RPE/BM) angulation, transverse neural canal diameter (NCD) and the highest vertical point of the internal limiting membrane from the transverse diameter (papillary height). The mean (±standard deviation) opening and closing CSF pressures were 34.3±11.8 and 11.6±3.3cmH2O, respectively. Mean RNFL thickness (pre LP: 196±105µm; post LP: 164±77µm, p=0.1) and transverse NCD (pre LP: 1985±559µm; post LP: 1590±228µm, p=2.0) decreased in all subjects, but with non-significant trends. The RPE/BM angle (mean change: 5.8±2.0degrees, p=0.003) decreased in all subjects. A decrease in papillary height was seen in three of five subjects (mean: pre LP: 976±275µm; post LP: 938±300µm, p=0.9). Our results show a measurable, objective change in the ONH after acute lowering of the lumbar CSF pressure, suggesting a direct link between the lumbar subarachnoid space and ONH regions, and its potential as a non-invasive method for monitoring intracranial pressures.

Clinical Validation of a Transcranial Doppler-Based Noninvasive Intracranial Pressure Meter: A Prospective Cross-Sectional Study.

BACKGROUND: Noninvasive intracranial pressure (ICP) measurement would represent a major advance for patients with neurological problems. The Vittamed ICP meter is an ultrasound-based device reported to have high agreement with lumbar puncture cerebrospinal fluid (CSF) pressure measurement. However, previous studies included mostly patients with normal levels of ICP. The purpose of our study was to perform an independent clinical validation study of a transcranial Doppler-based noninvasive ICP meter in patients anticipated to have a wide range of ICP. METHODS: In a prospective cross-sectional design, we simultaneously measured ICP with the Vittamed device and the invasive lumbar CSF pressure. The operator of each procedure was blinded to the result of the other method. Data were analyzed using Bland-Altman plots, Pearson correlation coefficients, and receiver operator characteristic curves. RESULTS: Twenty-four independent paired measurements of Vittamed and lumbar CSF pressure were obtained; with mean absolute difference between paired measures of 4.5 mmHg (standard deviation 3.1). The 95% limits of agreement were -10.5 to +11.0. The systematic bias (mean of paired differences) was negligible at 0.25 mmHg. The sensitivity, specificity, and area under the curve for ICP >20 mmHg were 0.73, 0.77, and 0.71, respectively. CONCLUSIONS: The Vittamed ICP meter had fair agreement with lumbar CSF pressure measurement. The wide limits of agreement would preclude using this version of the device as a stand-alone method for ICP determination, but may be useful if combined with other ICP screening methods. Ongoing improvements to the Vittamed hardware and software may lead to improvements in accuracy and clinical utility of this device.

Longitudinal Evaluation of Visual Function in Multiple Sclerosis.

PURPOSE: To evaluate longitudinal changes of visual function in relapsing-remitting multiple sclerosis (RRMS). METHODS: Multifocal visual evoked potential (mfVEP), contrast sensitivity (CS), and Humphrey visual fields (HVFs) were obtained at two visits (mean follow-up, 1.5 [±0.9] years) in both eyes of 57 RRMS patients (53 eyes with optic neuritis [ON]: 14 ON within 6 months of first visit [ON < 6 months] and 39 ON ≥ 6 months; 57 non-ON). Longitudinal changes were assessed using mfVEP amplitude (log signal-to-noise ratio [logSNR]), latency, CS, and HVF mean deviation based on established 95% tolerance limits of test-retest variability. RESULTS: A significant percentage of eyes in the ON < 6 months group exceeded 95% tolerance limits for mfVEP logSNR (21%, p < 0.05), latency (35%, p < 0.01), and CS (31% p < 0.001); more improved than worsened over time (14% vs. 7% for logSNR, 21% vs. 14% for latency, and 31% vs. 0% for CS). Multifocal visual evoked potential latency decreased in 11% of non-ON eyes and in 10% of eyes in the ON ≥ 6 months group, and increased in 21% and 10%, respectively (p < 0.01 for all). Latency changes correlated negatively with baseline latency (r = -0.43 and -0.45 for non-ON and ON ≥ 6 months; p = 0.0008). Although a nonsignificant percentage of non-ON and ON ≥ 6 months eyes exceeded tolerance limits for logSNR, CS, or HVF, logSNR and latency changes correlated, and both measures correlated with changes in CS (r = 0.47 to 0.79, p < 0.01). CONCLUSIONS: Multifocal visual evoked potential, particularly latency, is potentially useful for assessing neuroprotective and remyelinating strategies in RRMS.

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.

Reproducibility of multifocal visual evoked potential and traditional visual evoked potential in normal and multiple sclerosis eyes.

PURPOSE: To establish reproducibility of multifocal visual evoked potential (mfVEP) and traditional pattern-reversal VEP (tVEP) in normals and relapsing-remitting multiple sclerosis (RRMS). METHODS: mfVEP (60-sector dartboard) was recorded twice within a month in 40 normals and 40 RRMS patients [25 eyes with last optic neuritis (ON) ≥6 months, 34 non-ON]. mfVEP amplitude and latency (ms) were calculated as mean logSNR and median relative latency, respectively, for all 60 sectors (global) and 9 regions. tVEP was recorded (15', 60' and 120' checks) in subsets of 34 normals and 30 RRMS patients. tVEP N75-P100 amplitude (µV) and P100 latency (ms) were obtained. Reproducibility was evaluated using intraclass correlation coefficient (ICC) and test-retest variability (TRV). ICC ≥ 0.75 was considered good. RESULTS: ICCs for global and regional mfVEP were >0.80 in all groups. ICCs for tVEP were >0.75 for all except latency in ON (0.52-0.68). For mfVEP or tVEP, TRV for amplitude was similar among all groups; TRV for latency (ms) was larger in ON (5.3 for mfVEP global, 10.3 for 60' tVEP) compared with non-ON (3.1, 8.3) and normal (2.3, 5.7) (p < 0.05 for all). When tVEP was analyzed using similar methods as mfVEP (logSNR and relative latency), mfVEP global measures showed better ICC and TRV than tVEP in all groups. CONCLUSIONS: mfVEP and tVEP showed good reproducibility in normals and RRMS. TRV for mfVEP latency was larger in ON than normal or non-ON. mfVEP global latency's TRV was about half the respective values for tVEP in all groups, due to averaging of multiple responses.

Tracking changes over time in retinal nerve fiber layer and ganglion cell-inner plexiform layer thickness in multiple sclerosis.

BACKGROUND: Neurodegeneration plays an important role in permanent disability in multiple sclerosis (MS). OBJECTIVE: The objective of this paper is to determine whether progressive neurodegeneration occurs in MS eyes without clinically evident inflammation. METHODS: Retinal nerve fiver layer thickness (RNFLT) and ganglion cell-inner plexiform layer thickness (GCIPT) were measured using Cirrus optical coherence tomography (OCT) in 133 relapsing-remitting MS (RRMS) patients (149 non-optic neuritis (ON), 97 ON eyes, last ON ≥6 months). Ninety-three patients were scanned at two visits. Percentages of abnormal GCIPT vs RNFLT (<5% of machine norms) in cross-sectional data were compared. Relations between RNFLT/GCIPT and MS duration (cross-sectional) and follow-up time (longitudinal) were assessed. RESULTS: GCIPT was abnormal in more eyes than RNFLT (27% vs 16% p = 0.004 in non-ON, 82% vs 72% p = 0.007 in ON). RNFLT and GCIPT decreased with MS duration by -0.49 µm/yr (p = 0.0001) and -0.36 (p = 0.005) for non-ON; -0.52 (p = 0.003) and -0.41 (p = 0.007) for ON. RNFLT and GCIPT decreased with follow-up time by -1.49 µm/yr (p < 0.0001) and -0.53 (p = 0.004) for non-ON, -1.27 (p = 0.002) and -0.49 (p = 0.04) for ON. CONCLUSIONS: In RRMS eyes without clinically evident inflammation, progressive loss of RNFLT and GCIPT occurred, supporting the need for neuroprotection in addition to suppression of autoimmune responses and inflammation.