RESUMO
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.).
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Oftalmopatia de Graves/tratamento farmacológico , Receptor IGF Tipo 1/antagonistas & inibidores , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Diplopia/tratamento farmacológico , Método Duplo-Cego , Esquema de Medicação , Exoftalmia/tratamento farmacológico , Oftalmopatia de Graves/diagnóstico por imagem , Humanos , Análise de Intenção de Tratamento , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Órbita/diagnóstico por imagem , Receptor IGF Tipo 1/imunologia , AutorrelatoRESUMO
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.
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Exoftalmia , Oftalmopatia de Graves , Anticorpos Monoclonais Humanizados/uso terapêutico , Diplopia , Oftalmopatia de Graves/tratamento farmacológico , HumanosRESUMO
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.
Assuntos
Oftalmopatia de Graves , Doenças do Nervo Óptico , Anticorpos Monoclonais Humanizados/uso terapêutico , Ensaios Clínicos como Assunto , Diplopia/tratamento farmacológico , Oftalmopatia de Graves/tratamento farmacológico , Humanos , Doenças do Nervo Óptico/induzido quimicamenteRESUMO
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 .).
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Anticorpos Monoclonais/uso terapêutico , Oftalmopatia de Graves/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Receptor IGF Tipo 1/antagonistas & inibidores , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Complicações do Diabetes , Método Duplo-Cego , Exoftalmia/tratamento farmacológico , Feminino , Oftalmopatia de Graves/complicações , Humanos , Hiperglicemia/induzido quimicamente , Fatores Imunológicos/efeitos adversos , Análise de Intenção de Tratamento , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Qualidade de VidaRESUMO
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.
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Oftalmopatias Hereditárias/diagnóstico , Fibras Nervosas/patologia , Doenças do Nervo Óptico/diagnóstico , Papiledema/diagnóstico , Células Ganglionares da Retina/patologia , Adulto , Lâmina Basilar da Corioide/patologia , Diagnóstico Diferencial , Feminino , Humanos , Pressão Intraocular , Masculino , Pessoa de Meia-Idade , Disco Óptico/patologia , Curva ROC , Estudos Retrospectivos , Sensibilidade e Especificidade , Tomografia de Coerência Óptica/métodos , Adulto JovemRESUMO
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.
Assuntos
Oftalmopatias Hereditárias/diagnóstico , Fibras Nervosas/patologia , Disco Óptico/patologia , Doenças do Nervo Óptico/diagnóstico , Papiledema/diagnóstico , Células Ganglionares da Retina/patologia , Tomografia de Coerência Óptica/métodos , Ultrassonografia/métodos , Adulto , Estudos Transversais , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Curva ROC , Estudos RetrospectivosRESUMO
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.
Assuntos
Potenciais Evocados Visuais/fisiologia , Esclerose Múltipla/diagnóstico , Transtornos da Visão/diagnóstico , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fibras Nervosas/patologia , Neurite Óptica/diagnóstico , Reprodutibilidade dos Testes , Células Ganglionares da Retina/patologiaRESUMO
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.
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Sensibilidades de Contraste/fisiologia , Potenciais Evocados Visuais/fisiologia , Esclerose Múltipla/fisiopatologia , Neurite Óptica/fisiopatologia , Transtornos da Visão/fisiopatologia , Campos Visuais/fisiologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes de Campo VisualRESUMO
OBJECTIVE: Many long-duration astronauts develop signs of elevated intracranial pressure and have neuro-ophthalmological findings similar to idiopathic intracranial hypertension (IIH) patients. Some also present with nasal congestion and subjective olfactory impairment. We prospectively evaluated olfactory function in IIH patients and the effect of 6° head-down tilt, which simulates the headward fluid shifting in microgravity, as spaceflight analogues. DESIGN: Olfaction was tested for all subjects in upright and 6° head-down tilt positions using two different measures: University of Pennsylvania Smell Identification Test and Olfactory Threshold Sniffin' Sticks with phenylethyl alcohol. RESULTS: IIH patients (n=19) had significant impairment on both olfactory measures compared with matched controls (n=19). The olfactory threshold dilution levels were 9.07 (95% CI 1.85 to 5.81) and 3.83 (95% CI 7.04 to 11.10), p=0.001, and smell identification scores were 35.61 (95% CI 34.03 to 37.18) and 32.47 (95% CI 30.85 to 34.09), p=0.008, for control and IIH subjects, respectively. The threshold detection was mildly impaired in head-down tilt compared with upright position in the combined subjects (6.05 (95% CI 4.58 to 7.51) vs 6.85 (95% CI 5.43 to 8.27), p=0.004). CONCLUSIONS: We demonstrated that IIH patients have marked impairment in olfactory threshold levels, out of proportion to smell identification impairment. There was also impairment in olfactory threshold in head-down tilt compared with upright positioning, but not for smell identification. The underlying mechanisms for olfactory threshold dysfunction in IIH patients need further exploration.
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Transtornos do Olfato/complicações , Transtornos do Olfato/fisiopatologia , Pseudotumor Cerebral/fisiopatologia , Adulto , Estudos de Casos e Controles , Feminino , Decúbito Inclinado com Rebaixamento da Cabeça/fisiologia , Humanos , Masculino , Pseudotumor Cerebral/complicações , Limiar Sensorial/fisiologia , Adulto JovemRESUMO
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.
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Esclerose Múltipla Recidivante-Remitente/diagnóstico , Degeneração Neural , Neurite Óptica/diagnóstico , Células Ganglionares da Retina/patologia , Neurônios Retinianos/patologia , Adulto , Idoso , Estudos de Casos e Controles , Estudos Transversais , Progressão da Doença , Feminino , Humanos , Modelos Lineares , Modelos Logísticos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/patologia , Neurite Óptica/patologia , Prognóstico , Fatores de Tempo , Tomografia de Coerência Óptica , Adulto JovemRESUMO
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.
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Angioplastia com Balão , Hipertensão Intracraniana , Pseudotumor Cerebral , Feminino , Humanos , Masculino , Pseudotumor Cerebral/diagnóstico por imagem , Pseudotumor Cerebral/cirurgia , Constrição Patológica/terapia , Constrição Patológica/complicações , Cavidades Cranianas/cirurgia , Resultado do Tratamento , Stents/efeitos adversos , Estudos RetrospectivosRESUMO
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.
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Exoftalmia , Oftalmopatia de Graves , Adulto , Humanos , Anticorpos Monoclonais Humanizados/efeitos adversos , Oftalmopatia de Graves/tratamento farmacológico , Inflamação , Inibidores de Proteínas Quinases , Método Duplo-CegoRESUMO
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.
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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.
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Hipertensão Intracraniana , Pseudotumor Cerebral , Adulto , Constrição Patológica/cirurgia , Cavidades Cranianas/diagnóstico por imagem , Cavidades Cranianas/cirurgia , Feminino , Humanos , Pressão Intracraniana , Masculino , Pseudotumor Cerebral/complicações , Pseudotumor Cerebral/cirurgia , Estudos Retrospectivos , Stents , Resultado do TratamentoRESUMO
CONCLUSION: A cutoff value of 6.0â 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.
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Hipertensão Intracraniana/complicações , Hipertensão Intracraniana/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Neuroimagem/métodos , Convulsões/complicações , Adolescente , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Hipertensão Intracraniana/fisiopatologia , Masculino , Reprodutibilidade dos Testes , Estudos Retrospectivos , Convulsões/fisiopatologia , Sensibilidade e EspecificidadeRESUMO
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.
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Potenciais Evocados Visuais , Esclerose Múltipla Crônica Progressiva/diagnóstico , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Neurite Óptica/diagnóstico , Tomografia de Coerência Óptica , Testes de Campo Visual , Campos Visuais , Vias Visuais , Adulto , Axônios/patologia , Estudos de Casos e Controles , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Crônica Progressiva/patologia , Esclerose Múltipla Crônica Progressiva/fisiopatologia , Esclerose Múltipla Recidivante-Remitente/patologia , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Bainha de Mielina/patologia , Degeneração Neural/patologia , Degeneração Neural/fisiopatologia , Neurite Óptica/patologia , Neurite Óptica/fisiopatologia , Estimulação Luminosa , Valor Preditivo dos Testes , Tempo de Reação , Neurônios Retinianos/patologia , Sensibilidade e Especificidade , Acuidade Visual , Vias Visuais/patologia , Vias Visuais/fisiopatologia , Adulto JovemRESUMO
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.
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Corticosteroides/uso terapêutico , Antivirais/uso terapêutico , Paralisia de Bell/tratamento farmacológico , Oftalmopatias/diagnóstico , Nervo Facial/patologia , Paralisia Facial/diagnóstico , Paralisia de Bell/complicações , Oftalmopatias/complicações , Nervo Facial/anatomia & histologia , Paralisia Facial/complicações , Humanos , Modelos Neurológicos , Vias Neurais/anatomia & histologiaRESUMO
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.
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Esclerose Múltipla/complicações , Esclerose Múltipla/diagnóstico , Neurite Óptica/complicações , Polarimetria de Varredura a Laser/normas , Tomografia de Coerência Óptica/normas , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fibras Nervosas/patologia , Retina/patologiaRESUMO
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.
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Técnicas de Diagnóstico Oftalmológico , Potenciais Evocados Visuais , Esclerose Múltipla Crônica Progressiva/complicações , Esclerose Múltipla Recidivante-Remitente/complicações , Neurite Óptica/diagnóstico , Vias Visuais/fisiopatologia , Adulto , Estudos de Casos e Controles , Análise por Conglomerados , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Crônica Progressiva/fisiopatologia , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Neurite Óptica/etiologia , Neurite Óptica/fisiopatologia , Estimulação Luminosa , Valor Preditivo dos Testes , Curva ROC , Tempo de Reação , Recuperação de Função Fisiológica , Fatores de Tempo , Adulto JovemRESUMO
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)â¯>â¯6â¯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% (pâ¯=â¯0.33) in ON, 45% vs 22% (pâ¯<â¯0.0005) in non-ON. In ON and non-ON, mfVEP measures and CS correlated with GCIPLT and RNFLT (râ¯=â¯-0.24 to 0.78, pâ¯=â¯0.03-0.0001). In ON, mfVEP amplitude (C,G) correlated better with GCIPLT (râ¯=â¯0.78, 0.76) than RNFLT (râ¯=â¯0.43, 0.58; pâ¯<â¯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.