Peripapillary Hyperreflective Ovoid Mass-Like Structures: Multimodal Imaging – A Review
Jeffery RCH, Chen FK. Peripapillary hyperreflective ovoid mass-like structures: Multimodal imaging-A review. Clin Exp Ophthalmol. 2023;51:67–80.
Prior to the establishment of the Optic Disk Drusen Consortium the ovoid peripapillary structures detected on optical coherence tomography (OCT) were felt to be buried optic disk drusen. These structures have since been redefined as peripapillary hyperreflective ovoid mass-like structures (PHOMS) and identified as a manifestation of axoplasmic stasis.
The authors discuss the characteristic findings of PHOMS on multimodal OCT and review the literature pertaining to the co-existence of PHOMS with diseases other than optic disk drusen. These include papilloedema, anterior ischaemic optic neuropathy, tilted disk syndrome, inflammatory demyelinating disorders as well as retinal and orbital diseases.
David Bellows
Anti-Hypertensive Medications – Before Bed or Not?
Labowsky MT, Rizzo III JF. The controversy of chronotherapy: Emerging evidence regarding bedtime dosing of antihypertensive medications in non-arteritic anterior ischaemic optic neuropathy. Semin Ophthalmol. 2023;38:99–104.
This is a review article highlighting the marked conflict between therapeutic recommendations published in the ophthalmology and cardiology literature, with the former arguing against taking anti-hypertensive medications at bedtime to reduce risk of sequential non-arteritic anterior ischaemic optic neuropathy (NAION) while the latter arguing in favour of bedtime dosing to reduce the risk of cardiovascular disease (CVD).
The observation of “blinding upon awakening” in patients with NAION has prompted the postulations of nocturnal hypotension contributing to NAION development. Since then, studies have been conducted to identify such association with conflicting results. This review summarises the results in the literature evaluating nocturnal hypotension, blood pressure fluctuations and NAION throughout the years. One of the studies argued the blunted “morning surge” instead of nocturnal dip being the potential contributing factor in NAION. Nevertheless, the purported association between nocturnal hypotension and NAION has become widely accepted in ophthalmology. This aetiological belief has led to the recommendation to patients who have experienced NAION to refrain from bedtime dosing of anti-hypertensive medications to reduce the risk of sequential NAION.
This review also brings readers’ attention to the recent literature on benefit of bedtime anti-hypertensive dosing in the cardiology world. “Chronotherapy” is a term used for specific timing of medication dosing for therapeutic effect. In a meta-analysis of 153 human trials (1976–2020), beneficial effects of bedtime dosing were found in the majority of studies in terms of sleep time systolic blood pressure (BP), biomarkers of hypertension associated end-organ damage and adverse medication events. The benefit of bedtime anti-hypertensive dosing was further substantiated by two large scale prospective clinical trials looking at ingestion time and cardiovascular endpoints. Contrary to recommendations in the ophthalmic literature, mean elevation of asleep BP was a strong predictor of CVD. However, it is important to note that the ophthalmic complications reported in this trial only involved retinal artery thrombotic occlusion and not NAION.
It is therefore important for neuro-ophthalmologists to take note of this active and vibrant controversy while counselling patients who have lost vision due to NAION.
Noel Chan
International Diagnostic Criteria for MOGAD
Banwell B, Bennett JL, Marignier R, Kim HJ, Brilot F, Flanagan EP, et al. Diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease: International MOGAD Panel proposed criteria. Lancet Neurol. 2023;22:268–282.
The international diagnostic criteria for myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) was recently published in Lancet Neurology.
The MOGAD diagnosis criteria are:
(a) Core clinical demyelinating event: optic neuritis; myelitis; acute disseminated encephalomyelitis; cerebral monofocal or polyfocal deficits; brainstem or cerebellar deficits; or cerebral cortical encephalitis, often with seizures
(b) Positive MOG-IgG test on a cell-based assay
(c) Exclusion of better diagnoses including multiple sclerosis
Unlike the international diagnostic criteria for neuromyelitis optica spectrum disorder (NMOSD), published in 2015 that allows for a diagnosis of seronegative NMOSD, the diagnosis of MOGAD hinges on a positive MOG-IgG assay and does not propose a separate category of seronegative MOGAD. Therefore, the sensitivity of the MOG-IgG assay remains unclear. However, the specificity of the MOG-IgG assay has been well studied and is about 98%, with lower specificity and positive predictive values at the low titres of 1:20 and 1:40. Therefore, there are some nuances with the MOGAD diagnostic criteria, which largely hinges on the knowledge that the MOG-IgG assay is not 100% specific. If a patient has a high MOG-IgG titre, the presence of one of the core clinical demyelinating events will be enough to meet the criteria for a diagnosis of MOGAD. However, if a patient has a low MOG-IgG titre or have a positive MOG-IgG test in the cerebrospinal fluid but not in the serum, there must be clinical or radiological supportive findings suggestive of MOGAD. For example, findings that would help support a diagnosis of MOGAD optic neuritis include bilateral optic neuritis, longitudinal optic nerve enhancement, perineural optic sheath enhancement, and/or optic disc oedema. Clinical and radiological features supportive of MOGAD myelitis and brain attacks are also provided.
In summary, the international MOGAD criteria provide a large step towards having a uniform diagnosis of MOGAD. Additional clinical features of MOGAD may become recognised in the future to expand the phenotype of MOGAD, but it will be important to validate the more rare atypical presentations because false positive MOG-IgG results can occur, especially in low pre-test probability situations with low MOG-IgG titres.
John Chen
Increased Risk for Dementia or Alzheimer’s Disease Among Patients with Age-Related Macular Degeneration
Tsai HR, Lo RY, Liang KH, Chen TL, Huang HK, Wang JH, Lee YC. Risk of subsequent dementia or Alzheimer disease among patients with age-related macular degeneration: A systematic review and meta-analysis. Am J Ophthalmol. 2023;247:161–169.
The authors conducted a systemic review and meta-analysis to elucidate the association of age-related macular degeneration (AMD) with subsequent dementia or Alzheimer’s disease (AD). They enrolled a total of 8,223,582 participants from eight studies published during 2000–2021, with mean/median follow-ups ranging from 2 to 11 years. The main population comprised Asians, Whites, and African Americans. The results showed that AMD was significantly associated with subsequent dementia (pooled hazard ratio [HR] 1.22) and AD (pooled HR 1.21). In addition, the association was more significant in dry AMD, compared with wet AMD. The authors concluded that patients with AMD have higher risks of developing dementia or AD. Ophthalmologists may raise awareness of the possible co-morbidities in patients with AMD.
Hui-Chen Cheng
The Presence of Paracentral Acute Middle Maculopathy May Help in Differentiating Arteritic AION from Non-Arteritic AION
Mairot K, Gascon P, Stolowy N, Comet A, Attia R, Beylerian M, et al. Paracentral acute middle maculopathy as a specific sign of arteritic anterior ischaemic optic neuropathy. Am J Ophthalmol. 2022;248:1–7
The authors conducted a retrospective cross-sectional study to investigate the presence of paracentral acute middle maculopathy (PAMM) in patients with arteritic anterior ischaemic optic neuropathy (A-AION) and non-arteritic anterior ischaemic optic neuropathy (NA-AION). They enrolled 28 patients with NA-AION and 17 patients with A-AION during 2018–2022 in France. They found that four out of 17 patients with A-AION had PAMM, but none of the patients with NA-AION had PAMM (p = .0143). Therefore, the authors proposed that PAMM may be a distinctive sign of A-AION and it yields a specificity of 100% and a positive predictive value of 100% in diagnosing A-AION. In addition, the sensitivity and negative predictive value were 19.1% and 63.0%, respectively. The author concluded that PAMM demonstrated on macular spectral-domain optical coherence tomography is highly specific for A-AION, which may help in differentiating A-AION from NA-AION.
Hui-Chen Cheng
Vision Loss as a Presenting Feature of Chronic Inflammatory Demyelinating Polyneuropathy
Kruszewski AM, Tauqeer Z, Meer EA, Bautista SA, Cherayil NR, Cimino ME, et al. Vision loss as a presenting feature of chronic inflammatory demyelinating polyneuropathy: A case series. J Neuroophthalmol. 2023;43:48–54.
Optic nerve demyelination is a clinical feature of inflammation of the central nervous system (CNS), such as in multiple sclerosis. However, it can also be associated with peripheral nervous system (PNS) disorders. Other associated antibodies have been increasingly discovered, thereby expanding the clinical spectrum of the condition.
This article describes 4 patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and optic nerve involvement. Two cases (pale optic disc in one and papilloedema in another) tested positive for serum neurofascin-155 (NF155) IgG4 antibodies against paranodal proteins. NF155+ CIDP is unique because of the high frequency of demyelinating lesions in the CNS, as NF155 co-exists in the PNS and CNS. NF155+ CIDP usually presents with hypertrophy of the nerve roots and extremely high levels of cerebrospinal fluid proteins. The patients were treated with immunomodulatory therapy.
Panitha Jindahra
Ophthalmological Problems Correlate with Cognitive Impairment in Patients with Parkinson’s Disease
Zhang C, Wu QQ, Hou Y, Wang Q, Zhang GJ, Zhao WB, et al. Ophthalmologic problems correlate with cognitive impairment in patients with Parkinson’s disease. Front Neurosci. 2022;16:928980.
The authors studied 205 Chinese patients with Parkinson’s disease (PD) and 200 age-matched controls with the Visual Impairment in Parkinson’s Disease questionnaire (VIPD-Q) to identify pathogens that lead to visual impairment.
Ophthalmological symptoms were present in 57% of patients with PD versus 14% of controls and comparing visual impairment scores before and after deep brain stimulation showed that this procedure improved visual function.
Optical coherence tomography (OCT) examination was done to determine retinal nerve fibre layer (RNFL) thickness and found thinner RNFLs in cognitively impaired PD compared with non-PD patients without cognitive impairment. There was also a positive association between RNFL thickness and the Montreal Cognitive Assessment (MoCA) score and a negative correlation between the Unified Parkinson’s Disease Rating Score II (UPDRSII) score and RNFL thickness.
Vessel density analysed by vessel percentage area (VPA) was lower in the cognitively impaired group with a positive association between VPA and MoCA while perivascular spaces were higher in the high VIPD-Q group than in controls.
Ultimately, these findings suggest that patients with PD have a higher prevalence of ophthalmologic symptoms as reflected by high VIPD-Q. A simple eye examination may be an effective and non-invasive tool to predict and monitor cognitive change in patients with PD.
Peter MacIntosh
Dural Venous Sinus Thrombosis and Papilloedema Related to JAK2 Mutation
Donaldson L, Dhoot A, Margolin E. Dural venous sinus thrombosis and papilledema related to JAK2 mutation: A case series. Can J Neurol Sci. 2023;50:194–200.
The authors present a clinically-relevant series of four newly recognised JAK2 V617F mutation positive patients among 15 (26%) with confirmed dural venous sinus thrombosis (DVST) and papilloedema on examination over a 4 year period. One of the four had a pre-existing diagnosis of essential thrombocytosis while two others obtained a new diagnosis of polycythaemia vera (PCV) at the time of the DVST and JAK2 mutation diagnosis. Three of the four without a known myelodysplastic neoplasm diagnosis at the time of the DVST did not present with an obvious pro-thrombotic state. Case 1 was a 40-year-old woman who had been diagnosed 4 years previously with pseudotumor cerebri (PTC) before discovery of the DVST and review of neuro-imaging from the initial PTC diagnosis did not show a DVST. Case 2 was a 64-year-old man with incidentally found bilateral papilloedema on routine annual optometric examination. Case 4 had 1 year of increasing headaches and blurry vision before being found to have papilleodema, eventually leading to a DVST and JAK2 mutation diagnosis. Three of the four had an abnormal complete blood count (CBC) at presentation.
This case series highlights a potential blind spot in our diagnostic radar for patients presenting with papilloedema. According to the study discussion, the JAK2 V617F mutation was only initially recognised as a prominent cause of myeloproliferative neoplasms (essential thrombocytosis, PCV, and myelofibrosis) in 2005. More recently, JAK2 mutations have been noted to be a prominent cause of venous thrombosis including DVST, deep vein thrombosis, and portal vein thrombosis. Per the authors, other case series have found the rate of JAK2 mutations among those with DVST to be common at 6.6–11%. Interestingly, three of the four patients in this series had chronic presentations potentially mimicking chronic PTC including incidentally found papilloedema or symptoms of increased intracranial pressure lasting more than 1 year. I myself have cared for a 48-year-old female who met all criteria for PTC including a negative magnetic resonance venography (MRV) of her brain. Her disease proved resistant to acetazolamide and eventually testing the CBC led to the diagnosis of PCV and the JAK2 V617F mutation.
This case series builds an argument that all patients with papilloedema, regardless of the timing of symptoms, should undergo venography. Also, the CBC is an important test in the evaluation of papilloedema to screen for myelodysplastic neoplasms, and JAK2 mutations should be strongly considered in any patient presenting with DVST who does not have an alternative predisposing hypercoagulable risk factor after work-up.
Collin McClelland
Skin in the Game
Vaphiades MS, Grondines B, Kline LB, Riser E, Spencer D. Skin in the game. Surv Ophthalmol. 2023;68:308–311.
The authors reported a 23-year-old man with a history of migraine and focal seizures who presented with painless visual loss in the left eye associated with optic disk oedema. There was no recent history of cat exposure except for a cat that lived outside. Initial laboratory studies were negative. Magnetic resonance imaging of the brain and orbits without and with fat suppression and intravenous contrast was normal. The patient reported routinely skinning, processing and consuming deer while not wearing gloves, and he also frequently had cuts on his hands while doing so. The serum Toxoplasma gondii IgG antibody returned at >400 (normal range [NR] 0–7.1 IU/mL) with the IgM at 10.4 (NR 0–7.9 AU/mL). This case illustrates that, if unprotected with gloves, transdermal infection of toxoplasmosis can occur when processing venison. Since this case was written, other similar cases have been seen by the first author.
Michael Vaphiades
Optic Neuritis: Current Challenges in Diagnosis and Management
Benard-Seguin E, Costello F. Optic neuritis: Current challenges in diagnosis and management. Curr Opin Neurol. 2023;36:10–18.
The authors’ objective was to describe the clinical course, neuroimaging features, and relevant serological profiles of optic neuritis (ON), which is a broad term that describes an inflammatory optic nerve injury arising from a variety of potential causes, particularly from co-associated central nervous system inflammatory syndromes. These include multiple sclerosis, neuromyelitis optic spectrum disorders, and myelin oligodendrocyte glycoprotein antibody associated disease. These disorders vary with respect to their long-term prognosis and require different acute and chronic treatment strategies. Each disorder may result in permanent visual loss and neurological disability especially from relapses.
Michael Vaphiades
Is the Disease Risk and Penetrance in Leber’s Hereditary Optic Neuropathy Actually Low?
Mackey DA, Ong JS, MacGregor S, Whiteman DC, Craig JE, Lopez Sanchez MIG, et al. Is the disease risk and penetrance in Leber hereditary optic neuropathy actually low? Am J Hum Genet. 2023;110:170–176.
Pedigree analysis show that a large proportion of Leber’s hereditary optic neuropathy (LHON) family members who carry a mitochondrial risk variant never lose vision. Mitochondrial haplotype appears to be a major factor influencing the risk of vision loss in these patients. Analysis of the UK Biobank and Australian cohort studies found more than 1 in 1000 people in the general population carry either the m.14484T>C or the m.11778G>A LHON variants. None of the subset of carriers examined had visual acuity at 20/200 or worse, suggesting a very low penetrance of LHON.
Michael Vaphiades
Optic Neuritis and Autoimmune Optic Neuropathies: Advances in Diagnosis and Treatment
Bennett JL, Costello F, Chen JJ, Petzold A, Biousse V, Newman NJ, Galetta SL. Optic neuritis and autoimmune optic neuropathies: Advances in diagnosis and treatment. Lancet Neurol. 2023;22:89–100.
The authors discuss optic neuritis, an inflammatory optic neuropathy that is commonly indicative of multiple sclerosis, myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease, and neuromyelitis optica spectrum disorder. Regaining high-contrast visual acuity is common in people with idiopathic optic neuritis and multiple sclerosis-associated optic neuritis; however, residual deficits in contrast sensitivity, binocular vision, and motion perception might impair vision-specific quality-of-life metrics. In contrast, recovery of visual acuity can be poorer and optic nerve atrophy more severe in individuals who are seropositive for antibodies to MOG, aquaporin 4, and collapsin response mediator protein 5 than in individuals with typical optic neuritis from idiopathic or multiple-sclerosis associated optic neuritis. The authors note that imaging and laboratory findings can help differentiate these disorders, and guided by the early and accurate diagnosis of these optic neuritis subtypes, the timely use of high-dose corticosteroids and, in some instances, plasmapheresis could prevent loss of high-contrast vision, improve contrast sensitivity, and preserve colour vision and visual fields.
Michael Vaphiades
Temporal Dynamics of MOG Antibodies in Children with Acquired Demyelinating Syndrome
Wendel EM, Thonke HS, Bertolini A, Baumann M, Blaschek A, Merkenschlager A, et al. Temporal dynamics of MOG antibodies in children with acquired demyelinating syndrome. Neurol Neuroimmunol Neuroinflamm. 2022;9:e200035.
This multi-centre, prospective study included 116 children with initial acute central nervous system demyelinating syndromes and positive myelin oligodendrocyte glycoprotein (MOG) antibodies, who were followed over 5 years to study clinical and laboratory prognostic parameters for a risk of relapse and the temporal dynamics of MOG-IgG titres. Other than confirming that there was no significant association between disease course and MOG-IgG titres at onset, the new findings from this study include: seroconversion to MOG-IgG-negative within 2 years of the initial event showed a significant risk reduction for a relapsing disease course; and a decrease in MOG-IgG of ≥ 3 dilution steps after the first and second years was shown to be associated with a decreased risk of relapses. This study provided further evidence supporting monitoring MOG antibody status and titre in the paediatric MOGAD disease population.
Xiaojun (June) Zhang