Teprotumumab-related adverse events in thyroid eye disease
Shah, Shreya A, Amarikwa L, Sears CM, et al. Teprotumumab-related adverse Events in thyroid eye disease: a multi-centre study. Ophthalmology 2023.
This is an important paper for physicians treating thyroid eye disease. In 2020 the United States Food and Drug Administration (FDA) approved teprotumumab, a human anti-Insulin Growth Factor-1 R (IGF-1 R) monoclonal antibody, for the treatment of thyroid eye disease (TED). IGF-1 R is found, not only found in the orbital tissues, but in many other tissues throughout the body. The purpose of this article is to report on the adverse events (AE) associated with the use of teprotumumab in the treatment of thyroid eye disease.
This multicenter retrospective study looked at 131 patients who were treated with teprotumumab for TED. The authors categorised AEs into three grades. Grade 1 AEs (mild) required only monitoring without intervention, grade 2 AEs (moderate) required minimal intervention, and grade 3 AEs (severe) were considered disabling and/or requiring hospitalisation.
81.7% of patients experienced at least one AE with a median of 4 AEs per effected patient. Grade 1 AEs were reported in 74% of patients, grade 2 AEs were reported in 28.2% of patients, and grade 3 AEs were reported in 8.4% of patients. 46% of patients had at least 1 persistent AE at last follow-up (a mean of 70.2 weeks after the first infusion).
The most common AEs were muscle spasms (58%). 38.2% of patients experienced gastrointestinal AEs including diarrhoea, nausea, and others. 39% of patients developed skin disorders including alopecia, onycholysis, and rash. 31% experienced hearing and labyrinth disorders including hearing loss, tinnitus, autophony, and otalgia. 53% of patients with an AE reported complete resolution of their symptoms.
Space does not permit an exhaustive list of all AEs associated with teprotumumab. I encourage any physician who treats thyroid eye disease to read this important paper.
David Bellows
Optic nerve graduating as the 5th lesion site to diagnose multiple sclerosis?
Vidal-Jordana A, Rovira A, Calderon W, et al. Adding the optic nerve in multiple sclerosis diagnostic criteria: a longitudinal, prospective, multicentre study. Neurology. 2024;102:e207805.
Despite the frequent involvement of optic nerve, the 2017 revised McDonald diagnostic criteria for multiple sclerosis (MS) do not include an optic nerve lesion when evaluating dissemination in space (DIS) or dissemination in time (DIT). However, because the optic nerve was not considered as one of the CNS areas for DIS confirmation, the diagnosis of MS may be delayed in patients presenting with optic neuritis, who must have a lesion in 2 additional CNS areas (instead of 1 as for other types of CIS) to fulfil DIS criteria.
This is a longitudinal, multicentre, prospective study where MAGNIMS centres were invited to provide prospective data on patients with CIS who underwent a visual assessment within 6 months of onset. Modified DIS criteria were constructed by adding optic nerve assessment with ON-MRI, OCT, VEP or combination of any 2 of these tests as the fifth area of CNS respectively. Performance of these different DIS criteria were analysed using the diagnosis of MS according to the 2017 McDonald criteria as primary outcome and new T2 lesion or a second relapse as secondary outcome. A total of 157 patients were included where 38.2% presented with optic neuritis. At a mean follow up of 27.9 months, 70.7% were diagnosed with MS (2017 McDonald criteria). The modified DIS criteria with the addition of optic nerve as a new topography led to different degrees of improved sensitivity (92.5% with ON-MRI vs 88.2%), but decreased specificity (80.0% with GCIPL vs 82.2%) with an overall similar accuracy and area under the curve (AUC) when compared to the current 2017 DIS criteria.
Since 2018, there have been multiple retrospective single centre studies assessing the added value of optic nerve lesion to the current criteria. The strength of this current study is that apart from using VEP or clinical exam, other topographic findings were also analysed including increased signal intensity of optic nerve with dedicated ON-MRI, inter-eye asymmetry of peripapillary retinal nerve fibre layer (RNFL) of ≥5 μm and macular ganglion cell inner plexiform layer (GCIPL) thickness of ≥4 μm by OCT scans performed between 3–6 months from onset. The 2 tests capturing the highest rates of asymptomatic optic nerve lesions were pRNFL thickness and VEP. Of note, both OCT and VEP have been reported to be influenced by lesions in the posterior optic radiations. There is therefore a possibility that the abnormal results reported in this study are not capturing exclusively lesions in the anterior optic pathway but a damage along the visual system.
The authors proposed that the slight drop in specificity in all the modified DIS criteria may be contributed by the relative short follow up duration (~3 years) of their cohort. In addition, the modified DIS criteria might have increased the proportion of patients with optic neuritis CIS which has been described to have a better prognosis and thus might need additional time to reach both outcomes. Therefore, the authors do not only support the inclusion of optic nerve in the next revision of the diagnostic criteria but also suggests the evaluation of optic nerve to be done by either a dedicated ON-MRI sequence, OCT and/or VEP. It is however important to remark that all 3 tests should be performed meeting international guidelines and quality standards while being interpreted by experienced readers. Another point of note is that VEP performs better in the acute phase while OCT should be performed at least 3 months after the acute phase. The choice of the tests can be based on centre’s availability and expertise as well as time elapsed since CIS.
Noel Chan
Serum CGRP as biomarker for ophthalmoplegic migraine?
Takkar A, Kumar A, Katoch D, et al. Serum calcitonin gene-related peptide is elevated in patients with migraine and ophthalmoplegia. J Neuroophthalmol. 2023;43:399–405.
Calcitonin gene-related peptide (CGRP) containing nerves innervate the cerebral arteries and has a role in mediating vasodilation of cerebral and dural vessels during a migraine attack. It is believed that migraine ictus triggers the release of CGRP from these nerve fibres while a modest elevated CGRP level can occur during interictal phases with abnormal neurogenic vascular control. This is a case-control study assessing serum CGRP levels in patients with ophthalmoplegia migraine (OM). Among 15 patients recruited, all had migraine without aura according to ICHD-3 diagnostic criteria and none of the participants were on long term prophylaxis for migraine at presentation. All experienced an antecedent worsening of migraine of 28–56 days (median 35 days) prior to the onset of ophthalmoplegia. A single oculo-motor or abducens nerve was affected in 3 and 12 patients respectively with a median duration of ophthalmoplegia of 35 days. During the ictal phase, the median serum CGRP levels were significantly elevated in this cohort of patients as compared to age & sex matched controls. The ictal phase serum CGRP levels were also found to be positively correlated with the duration of ophthalmoplegia. Therefore, the study findings offer positive evidence to suggest a migrainous pathology in the painful ophthalmoplegia during the migraine attack. The authors hypothesised that in patients with OM, the inflammation is significant enough to cause functional nerve deficits but may not result in structural changes visible on imaging. They suggested OM or recurrent painful ophthalmoplegic neuropathy (RPON) as a subtype of migraine with the potential of using CGRP level as a biomarker for OM diagnosis.
Noel Chan
Is topical elamipretide an effective treatment for lHON?
Karanjia R, and Sadun AA. Elamipretide topical ophthalmic solution for the treatment of subjects with leber’s hereditary optic neuropathy: a randomised trial.” Ophthalmology. 2023.
This was a randomised clinical trial evaluating topical elamipretide for the treatment of Leber’s Hereditary Optic Neuropathy (LHON). Elamipretide is a mitochondrial-targeted tetrapeptide that interacts with cardiolipin to stabilises the structure and function of the mitochondrial electron transport chain. In this phase 2 trial, prospective, randomised, double-masked, single centre trial (University of California at Los Angeles), LHON patients with the m.11778 G > A mutation with vision loss between 1 and 10 years prior to enrolment were randomised into three groups: 1% topical elamipretide bid OS (placebo in the other), 1% topical elamipretide OD (placebo in the other), and 1% topical elamipretide bid OU for 52 weeks followed by an open label extension (OLE) for an additional 108 weeks.
A total of 8 patients received single-eye elamipretide and 4 received elamipretide in both eyes. While elamipretide was well tolerated with only mild to moderate adverse events, there was no significant change in the best corrected visual acuity (BCVA) in the elamipretide-treated eyes at any time point compared to placebo. However, post-hoc analysis showed a mild improvement in mean deviation in the central field in the elamipretide-treated eyes compared to placebo. Colour discrimination and contrast sensitivity mildly improved in the OLE, but was not significantly different between elamipretide and placebo. Overall, there was a mild improvement reported in the visual function questionnaire (VFQ-39) over the course of the trial.
The main limitations of the trial included the small sample size and only inclusion of LHON patients in the more chronic phases of vision loss. There were also no patients that received placebo in both eyes, and therefore the improvement in VFQ-39 could not be definitively attributed to elamipretide treatment.
In summary, this randomised clinical trial demonstrated that topical elamipretide was well tolerated, but did meet its primary endpoint of improvement in BCVA. However, there were mild improvements in central visual fields suggesting there may be some benefit of elamipretide. It is important to note that this trial only included LHON patients who had vision loss for at least one year prior to enrolment. It is possible that earlier treatment during the more dynamic phase may have a more beneficial effect, as has been speculated for idebenone treatment in LHON. Future studies are warranted to explore the potential benefit of elamipretide for LHON patients.
John Chen
Glaucoma patients may have increased risks of developing dementia: a population-based study from sweden
Crump C, Sundquist J, Sieh W, Sundquist K, Risk of Alzheimer’s disease and related dementias in persons with glaucoma: a national cohort study. Ophthalmology. 2023. Article in Press
The authors conducted a national matched cohort study to investigate the risk of dementia following glaucoma diagnosis. A total of 324,730 persons diagnosed with glaucoma and 3,247,300 age- and sex-matched population-based controls during 1995–2017 in Sweden were enrolled in this study. In 16 million person-years of follow-up, 10% of persons with glaucoma and 7% of controls were diagnosed with dementia. Persons with glaucoma had increased risks for Alzheimer’s disease (AD) (adjusted hazard ratios(HR), 1.39), vascular dementia (VaD) (adjusted HR, 1.66), and all-cause dementia (adjusted HR 1.57) using Cox regression analysis. Both primary open-angle and normal-tension glaucoma were correlated with increased risk for AD (adjusted HR, 1.31 and 1.28, respectively) and VaD (adjusted HR, 1.61; and 1.39, respectively). Primary angle-closure glaucoma was associated with VaD (adjusted HR, 1.26) but not AD (adjusted HR 0.98). The results had no gender predilection. Patients diagnosed with glaucoma at ages ≥70 had highest risks of developing dementia. The authors suggested that monitoring for dementia in patients with glaucoma may be needed for earlier detection and management of dementia.
Hui-Chen Cheng
Acetylcholinesterase inhibitors may reduce the risk of developing age-related macular degeneration in patients with alzheimer disease
Sutton SS, Magagnoli J, Cummings TH, Hardin JW, Ambati J, Alzheimer disease treatment with acetylcholinesterase inhibitors and incident age-related macular degeneration. JAMA Ophthalmol. 2024. Article in Press.
The authors aimed to investigate if the use of acetylcholinesterase inhibitors (AChEIs), commonly prescribed for Alzheimer disease (AD) and having anti-inflammatory effects, influence the incidence of age-related macular degeneration (AMD). They conducted a retropective propensity score–matched cohort study at health care facilities within the US Department of Veterans Affairs health care system from 2000 to 2023. Patients diagnosed with AD between 55 and 80 years-old with no pre-existing diagnosis of AMD were enrolled in this study. They finally enrolled 21,823 veterans with AD, with a mean age of 72.3 years, and 97.7% of them were male. The results of propensity score–matched Cox model showed that each additional year of AChEI treatment was associated with a 6% lower hazard of AMD (hazard ratio, 0.94; 95% CI, 0.89–0.99). The authors concluded that a small reduction in the risk of AMD among AD veterans receiving AChEIs was observed. Because of the limited population and gender predilection, further research is required to validate the findings and determine the causal relationships.
Hui-Chen Cheng
Weight management communications in idiopathic intracranial hypertension
Abbott S, Denton A, Wong SH, Mollan SP, Bul KC. Weight management communications in idiopathic intracranial hypertension: challenges and recommendations from the patients’ perspective. BMJ Neurol Open. 2023;5(2):e000527. doi:10.1136/bmjno-2023-000527. PMID: 38116470; PMCID: PMC10729070.
Despite the fact that neuro-ophthalmologists, neurologists, and ophthalmologists routinely care for idiopathic intracranial hypertension (IIH) patients and counsel them on the importance of weight loss in the long-term management of the disease, little if any formal training is provided in neurology and ophthalmology residency on how to optimally approach this sensitive topic with patients. Surprisingly, until this publication there was a lack of previously published studies regarding IIH patient perspectives on health care professional (HCP) performance in discussing weight loss for IIH. This study based out of the United Kingdom utilised the online SurveyMonkey platform to survey 625 adult IIH patients who had previously been advised to lose weight by one or more HCPs [most commonly neurologists (88%) and ophthalmologists (50%)] using both closed questions and open free-text questions that were subsequently analysed by the authors for trends.
Overall only 20% of respondents were content with how weight was discussed by HCPs and 21% felt the HCP was empathetic and supportive about weight management. IIH patients felt that HCPs should ask for permission before discussing weight but this approach was utilised by only 7% of HCPs. 22% of respondents reported that HCPs offered some form of specific weight management support (most commonly referral to a nutritionist/dietitian and a state funded weight loss program). Only 30% of IIH patients reported being provided a specific weight loss target by HCPs.
As a practicing neuro-ophthalmologist, I found this simple study to be profoundly thought-provoking because it quantifies and validates my previous gestalt that HCPs caring for IIH as a whole (myself included) are providing inadequate and ineffective counselling on weight loss which remains the most important long-term treatment for IIH. The authors admit the study suffers from the usual weaknesses of online-survey data including excluding patients with less digital literacy and access to digital media, recall bias due to a potentially long period between appointments related to IIH and taking the survey, as well as a lack of objective data regarding demographics and disease severity among the self-reported IIH patients completing the survey. Additionally patient perception of performance among HCPs does not precisely equate to objective HCP performance particularly in the discussion of ultra-sensitive topics such as body weight. It may be that for some IIH patients there is not an effective way to approach this topic without evoking negative emotions.
While there may be no single perfect approach to the challenging discussion of weight loss among IIH patients, in my opinion this study should be required reading for any HCP who treats IIH patients. Much like surgeons carefully prepare, rehearse, and modify their pre-surgery consent discussion over time, all HCPs who care for IIH patients should formally prepare and routinely update their discussion of weight and weight loss for IIH. This study provides an excellent framework to create a more effective dialogue with IIH patients by providing specific recommendations on content that should be included in such a talk (e.g., verbal consent to discuss weight, specific weight loss target, explanation of weight as a risk factor for IIH being a biologic phenomenon, specific weight loss management options) as well as avoiding approaches that might be emotionally traumatic to the patient (e.g. using terminology such as “obese” or “fat” and avoiding blame).
Collin McClelland
Systematic review exploring the clinical features of optic neuritis after SARS-CoV infection and vaccination
Georganta I, Chasapi D, Smith CJ, Kopsidas K, Tatham A. Systematic review exploring the clinical features of optic neuritis after SARS-CoV infection and vaccination. BMJ Open Ophthalmol. 2023;8(1):e001336.
The authors performed a literature search in four databases (PubMed, Medline, Embase and Google Scholar) to identify relevant case reports and case series of optic neuritis (ON) following SARS-CoV-2 infection and vaccination. Sixty-eight studies were found to be eligible for inclusion, including 34 reporting ON following SARS-CoV-2 infection and an equal number reporting cases postvaccination. In total 93 patients and 125 eyes were included. The infection cohort included 42 patients and 56 eyes, 51.2% were female and 33.3% experienced bilateral ON. The mean visual acuity was 1.64 log of minimum angle of resolution (LogMAR), while pain was present in 77.8%. Oligoclonal bands were present in 3 patients, myelin oligodendrocyte glycoprotein (MOG) antibodies in 18 patients and AQP-4 antibodies in 4 patients. The vaccination cohort included 51 patients and 69 eyes. 60.8% were female and 35.3% had a bilateral ON. The mean visual acuity was 0.93 LogMAR. Oligoclonal bands were present in 46.7%, MOG antibodies in nine patients and AQP-4 antibodies in three patients. The authors concluded that patients with ON post-SARS-CoV infection were more likely to experience severe visual impairment than in cases following vaccination. However, in order to demonstrate causality, a putative correlation between COVID-19 infection and ON should also be established, with consideration to potential confounding factors.
Michael Vaphiades
Prevalence of serum MOG antibody and AQP4 antibody in optic neuritis After SARS-CoV-2 infection
Sun CB. Prevalence of serum MOG antibody and AQP4 antibody in optic neuritis after SARS-CoV-2 infection. Front Immunol. 2023;14:1296518.
The authors prospectively studied 35 patients clinically diagnosed as optic neuritis (ON) and laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to evaluate the prevalence of serum myelin oligodendrocyte glycoprotein antibody (MOG-Ab) and aquaporin-4 antibody (AQP4-Ab) in this patient population using a cell-based indirect immunofluorescence assay (CBA). Thirty-three and two cases showed positive SARS-CoV-2 RNA test results before or shortly after ON onset, respectively. ON occurred unilaterally in 24 cases and bilaterally in 11 cases. Ophthalmic examination revealed swollen optic disc in 37 eyes, normal optic disc in 6 eyes, and temporally or wholly paled optic disc in 3 eyes. CBA revealed seropositive MOG-Ab in 10 cases and AQP4-Ab in 2 cases, respectively, of which 2 AQP4-Ab-seropositive cases and 1 MOG-Ab-seropositive case had a past medical history of ON. Most ON patients showed a rapid and dramatic response to pulse steroid therapy. The median of BCVA at the onset and at the last follow-up was 20/500 (ranging from light perception to 20/20) and 20/67 (ranging from counting fingers to 20/20), respectively. Serum MOG-Ab and AQP4-Ab were detected in 28.6% (10/35) and 5.7% (2/35) cases after SARS-CoV-2 infection. The authors concluded that their study supports that SARS-CoV-2 infection-related ON is a post-infectious immune mediated inflammatory process which responds to pulse steroid therapy.
Michael Vaphiades
Utility of ChatGPT for automated creation of patient education handouts
Tao BK, Handzic A, Hua NJ, Vosoughi AR, Margolin EA, Micieli JA. Utility of ChatGPT for automated creation of patient education handouts: an application in neuro-ophthalmology. J Neuroophthalmol. 2024. doi:10.1097/WNO.0000000000002074. Epub ahead of print. PMID: 38175720.
ChatGPT (OpenAI, San Francisco) may assist with automating production of patient handouts on common neuro-ophthalmic diseases. The authors queried ChatGPT-3.5 to generate 51 patient education handouts across 17 common neuro-ophthalmic conditions. They devised the “Quality of Generated Language Outputs for Patients” (QGLOP) tool to assess handouts on the domains of accuracy/comprehensiveness, bias, currency, and tone. The mean QGLOP corresponded to a performance of 74.4% which would require moderate revision. A fellowship-trained neuro-ophthalmologist scored each passage. Handout readability was assessed using the Simple Measure of Gobbledygook (SMOG), which estimates years of education required to understand a text. The authors discovered that a fellowship-trained ophthalmologist may have at-least a moderate level of satisfaction with the write-up quality conferred by ChatGPT and it should be used as an efficiency tool to generate an initial draft for the neuro-ophthalmologist, who may then edit and refine the accuracy and readability for a lay readership. This is an example of how AI can aid in medicine without overstepping or supplanting the physician role in patient care.
Michael Vaphiades
Ophthalmoplegia associated with extramedullary multiple myeloma
Dhanani U, Mortensen PW, Raviskanthan S, Lee AG, Whyte AT, Gombos DS, Al-Zubidi N. Ophthalmoplegia associated with extramedullary multiple myeloma: case series from a tertiary cancer centre. J Neuroophthalmol. 2024. doi:10.1097/WNO.0000000000002076. Epub ahead of print. PMID: 38175728.
Multiple myeloma (MM) is a malignant disorder of plasma cells that results in tumour cells replacing the bone marrow. In extramedullary MM (EMM), tumour cells proliferate outside the bone marrow. EMM may produce ophthalmoplegia through direct invasion of the superior orbital fissure, cavernous sinus, and/or sphenoidal sinus. The authors retrospectively reviewed the medical records of 7 patients at MD Anderson Cancer Center who suffered from ophthalmoplegia secondary to extramedullary MM between 2019 and 2021. Skull base MRI revealed 4 patients with ophthalmoplegias secondary to superior orbital fissure invasion, 2 patients with ophthalmoplegias secondary to cavernous sinus invasion, and 1 patient with ophthalmoplegia secondary to sphenoid sinus invasion. All 7 patients were treated effectively with palliative radiation therapy (with or without chemotherapy), and the efficacy of this treatment correlates with what has been described previously in the literature. Two of the patients described in this case study died from complications of EMM or their associated treatment plan. Infiltration of MM to the cavernous sinus is extremely rare and portends advanced stage disease that carries a poor prognosis and is associated with treatment resistance. The authors concluded that reporting such cases will allow for increased awareness and more prompt treatment of this disease process.
Michael Vaphiades
Inclusion of optic neuritis in dissemination in space improves the performance of McDonald 2017 criteria in hispanic people with suspected multiple sclerosis
Amezcua L, Robers MV, Soneji D, Manouvakhova O, Martinez A, Islam T. Inclusion of optic neuritis in dissemination in space improves the performance of McDonald 2017 criteria in Hispanic people with suspected multiple sclerosis. Mult Scler. 2023;29(14):1748–1754. doi:10.1177/13524585231209016. Epub 9 November 2023. PMID: 37942880.
This study adds more data supporting improved performance of McDonald 2017 criteria for MS by including optic neuritis (ON) in dissemination of space. Of note, this study included 102 cases of CIS suspected as MS, 28 of 35 cases with clinically reported ON were confirmed by paraclinical objective data including MRI, OCT and/or VEP. Compared to all 35 cases with reported ON, the sensitivity, diagnostic accuracy and also the specificity further improved in this group of 28 ON patients. I believe this data helps address the initial concern of including ON in DIS due to diagnosis inaccuracy of ON due to lacking standardised objective measurements. One point I noticed in this study that might lead to questions is the validation of diagnosis of MS used in this study was at 36 months follow up visit from initial presentation, and I was not able to find during this period of follow up time if those 9 additional identified patients, who were considered as false negative, developed further clinical events or new lesions on MRI. Nevertheless, for neuro-ophthalmologists who often are the initial healthcare provider seeing ON patients, this study provides further evidence to support early diagnosis of MS and more aggressive approach regarding starting DMT.
Xiaojun Zhang