Clinical features, diagnosis, and types of optic neuritis

INTRODUCTION

Inflammation affecting the optic nerve can be termed optic neuritis. Different conditions can contribute to optic neuritis, including systemic and central nervous system (CNS) disorders. Besides, estimates show that the condition's incidence is variable and ranges between 1.4-33 per 100,000 population. The estimated rates vary based on different factors. These include population demographics, efficient detection of cases, and accurate diagnosis.^1-5 On the other hand, evidence shows that errors in the evaluation and diagnosis of the presenting patients might also contribute to different reported rates.⁶

Establishing a proper diagnosis and identifying the underlying etiology of optic neuritis can be challenging in clinical settings. This is due to the various subtypes and etiologies that were reported for the condition. However, conducting a thorough examination and the laboratory and imaging modalities can significantly enhance the diagnosis.⁷ In addition, some features, like old age, location of optic nerve damage, and bilateral involvement of this damage can add to the diagnosis of specific conditions. Therefore, it is essential to be adequately aware of the different subtypes of optic neuritis and distinguish between the different clinical features and diagnostic findings of each subtype to properly diagnose and enhance management of affected cases.⁸ Therefore, present literature review aims at discussing the clinical features and diagnosis of different types of optic neuritis according to findings from relevant studies in literature.

LITERATURE REVIEW

This literature review is based on an extensive literature search in Medline, Cochrane, and EMBASE databases which was performed on 27^th October 2021 using medical subject headings (MeSH) or a combination of all possible related terms, according to the database. To avoid missing potential studies, a further manual search for papers was done through Google scholar while reference lists of initially included papers. Papers discussing clinical features, diagnosis, types of optic neuritis were screened for useful information. No limitations were posed on date, language, age of participants/ publication type.

DISCUSSION

Clinical features and diagnosis

Evidence shows that having adequate knowledge about optic neuritis's clinical characteristics is essential to achieve preliminary diagnosis and management to avoid diagnosis-related errors. It is widely known that clinical features of patients mainly make diagnosis of patients with optic neuritis. However, clinical characteristics of patients with optic neuritis have been hugely variable based on type and etiology of condition (Figure 1). Accordingly, we will discuss these features based on the type and etiology of condition for a better illustration.⁷

Types

Optic neuritis secondary to multiple sclerosis

Estimates show that 75% of patients with multiple sclerosis usually suffer from optic neuritis. Besides, reports indicate that 25% of these patients typically present as the initial condition. The condition usually progresses within one or two weeks, painful and unilateral. However, it has been demonstrated that severe vision loss and bilateral optic neuritis are rare in these events. Other uncommon features are vitreal cells, retinal exudates, hemorrhagic disc edema, and optic disc edema. The estimated frequency for these events is 3.3%, 1.8%, 5.6%, and 35%, respectively.^9,10 A previous study also showed that optical coherence tomography (OCT) showed mild segmental swelling that is >110 of the physiological thickness of the peripapillary retinal nerve fiber layer. This might persist for at least one month in 58% of the affected eyes and is usually found in 82% of optic neuritis cases secondary to multiple sclerosis.^11,12 Many changes were also reported one month after the presentation. These include a mean visual field deviation of ≤ −15 dB, which can significantly predict the potential progression of the case to vision loss after six months.¹³ Other changes include reduced contrast sensitivity (< 1 log units) and reduced visual acuity (≤ 20/50). T1 gadolinium enhancement can also be used to assess some diagnostic findings. It has been reported that the associated lesion is usually anterior and short when compared to the lesions with myelin oligodendrocyte glycoprotein (MOG) and neuromyelitis optic spectrum disorder (NMOSD)-induced optic neuritis.^14-16 These lesions can be observed within 20 days from vision loss in 20% of the cases with multiple sclerosis. The 2017 McDonald criteria can also assess MRI of the brain and CSF analysis of these cases.¹⁷ MRI lesions can provide sufficient evidence regarding the presence of multiple sclerosis, adding to the diagnostic value. The major characteristics of optic neuritis in these situations include the presence of dissemination in addition to the clinical features associated with optic neuritis.

MOG-positive and NMOSD-induced optic neuritis

Estimates show that this condition is usually bilateral (ranging between 37 to 44% of the cases), has no ethnic differences, and is more common among females (with an estimated rate of 57%).^18,19 Studies also show that the age of onset of the condition is variable and the clinical features might vary based on the age of the affected patients. For instance, it has been shown that unilateral optic neuritis is more common among patients aged 20-45 years old. On the other hand, it has been reported that bilateral optic neuritis is more common among older adults. In addition, estimates show that in 25% of the affected cases, a concurrent presence of transverse myelitis-like NMOSD and optic neuritis is usually detected. In children, recurrent optic neuritis and acute disseminated encephalomyelitis (ADEM) are the main presentations of IgG-MOG condition.^18,19 Previous studies have reported that the associated vision loss in these cases is usually characterized by optic disc edema, being painful and severe (in 86% of the cases).^18,20 Perineural enhancements and extensive longitudinal optic nerve lesions are the most common MRI findings of IgG-MOG-induced optic neuritis, affecting 50% and 80% of the cases, respectively (Figure 2). It has been furtherly demonstrated that the condition is usually steroid dependant and also responds to steroid treatment. Besides, estimates indicate that the incidence of developing severe vision loss is rare when the underlying pathology has been observed once. Accordingly, the high rate of severe vision loss is attributed to recurrent episodes of optic neuritis.^19,20 Optic neuritis has been reported among patients with seropositive and negative QP4-IgG NMOSD patients.²¹ MRI can show diagnostic findings. However, it has been demonstrated that optic edema is usually rare. Moreover, vision loss might be associated with 20% of the cases and is usually bilateral and severe.^22-24 CSF findings are also abundant in the affected patients. It has been demonstrated that QP4-IgG seropositive patients are at increased risk of recurrence.²¹

Recurrent idiopathic optic neuritis

The first report of autoimmune optic neuritis was first introduced to the literature by Dutton et al.²⁵ The clinical characteristics of the condition include infrequent painful sensation and mild-to-moderate loss of visual acuity. Mild edema might also manifest on fundus examination. Imaging and laboratory investigations have been reported to be of limited value. However, evidence shows that cardiolipin antibodies and antinuclear antibodies (ANA) are usually found in the affected patients. In addition, it has been reported that histopathologic vasculitis might be detected by skin biopsy (25%). In other cases, complement deposition, immune complex, and immunoglobulins are usually found.²⁶ Bilateral or unilateral, spontaneous unresponsive attacks and isolated optic neuritis has been reported with relapsing isolated optic neuritis ²⁷. Females are predominantly are the most commonly affected, and evidence shows a low rate of systemic involvement (14%). Moderate vision loss was also reported in these cases (20/80).^28-30 Reports also show that CSF oligoclonal bands and pleocytosis are not commonly found. Moreover, ANA can be detected in 15% of the cases only.

On the other hand, it has been demonstrated that the presence of progressive vision loss together with recurrent isolated attacks of bilateral unilateral optic neuritis refers to chronic relapsing inflammatory optic neuropathy.³¹ The condition was primarily reported as steroid-dependant. However, more recent evidence shows that prevention requires the administration of immunosuppressive modalities. It has been furtherly demonstrated that patients usually have severe vision loss. Other characteristics are similar to the ones reported with relapsing isolated optic neuritis.^27,31,32

Optic neuritis owing to systemic conditions

Evidence shows that optic neuritis usually develops as a paraneoplastic condition, which is also correlated with CRMP-5/CV-2.³³ The condition is usually found in cases of small cell carcinoma. However, it has been reported that other tumors might also induce optic neuritis, including thymoma, lung adenocarcinoma, renal cell carcinoma, and prostate cancer.^33,34 The reported vision loss in these cases usually develops within weeks or months, progressive, and subacute. However, the condition is not painful. Fundus examination might indicate the presence of optic disc edema, vitreitis, and associated hemorrhagic features. In addition, the disease is usually associated with other central and peripheral manifestations that can help with the condition's diagnosis.³⁵ Systemic lupus erythematosus (SLE) can also predispose to the development of isolated optic neuritis. However, estimates indicate that the condition is not common in these events.^36,37 This has been displayed in a previous investigation, which showed that only 4.3% of cases with SLE have CNS involvement. Among these cases, it has been reported that optic neuritis is present in 8.7% of them. The condition is usually severe with incomplete recovery.

Moreover, a worse prognosis can be elicited by the presence of associated antiphospholipid or vasculitis disorders. This might be detected by potentially observing ischemic anterior optic neuropathy and optic disc edema.^38,39 Optic neuritis was also reported with patients with Sjögren syndrome. However, evidence indicates that CNS involvement in these cases is usually rare (5%), and optic neuritis is usually reported in 4% of these cases.⁴⁰ Recurrency has been reported in around one-third of the affected patients, and evidence indicates that the prognosis of the condition is variable. At the same time, most cases can be treated with corticosteroids. In these patients, evaluating the presence of AQP4 autoantibodies should be conducted in cases when NMOSD is associated.³⁹

Optic neuritis wing to infections and granulomatous disorders

Various infections can predispose to the development of optic neuritis. The most common conditions include neuroretinitis, which has been reported secondary to many bacterial and viral infections.⁴¹ Vision loss is usually painless and central. Therefore, OCT might be diagnostic, and most cases resolve spontaneously.^41,42 Lyme disease, syphilis, and tuberculosis were also reported to predispose to the development of optic neuritis.⁴³ CSF analysis might be of great value in cases with syphilis. It usually shows intrathecal IgG synthesis, elevated protein levels, and lymphocytic pleocytosis. Optic neuritis was also reported secondary to different viral infections. These include rubella, measles, mumps, dengue fever, West Nile virus, HIV, Epstein-Barr virus, cytomegalovirus, varicella-zoster virus, and herpes simplex virus.⁴⁴ Many of these infections affect immunocompromised patients, and evidence shows that many of them might respond to corticosteroid therapy. Moreover, it has been reported that vision loss is usually bilateral in cases with cytomegalovirus and Epstein-Barr viral infections. Accordingly, the clinical characteristics of the affected patients should be evaluated according to the underlying etiology.⁴³

Optic neuritis secondary to granulomatous diseases was also evidenced in the literature. For instance, in cases with granulomatosis with polyangiitis, it has been reported that optic neuritis might be present. The disease is usually bilateral, and vision loss is severe. The reported characteristics of the condition include diplopia, occlusion of the central retinal vein, chorioretinal ischemia, vasculitis. Other features include vitreitis, uveitis, orbital cellulitis, dacryoadenitis, and ulcerative conjunctivitis.^45,46 Optic neuritis might also be associated with sarcoidosis. In these events, evidence shows that around half of cases are unilateral and bilateral cases are usually asynchronous. Retinal vasculitis (also known as candle-wax droppings), macular exudates, infarcts to the nerve fiber layer, and vitreitis are frequently observed changes. CSF and MRI can also add to the diagnostic value of the condition.^47,48

CONCLUSION

Optic neuritis is a severe condition that can lead to permanent vision loss. In the present literature review, we have discussed the potential clinical features and diagnostic findings of the different types of optic neuritis. More severe cases of optic neuritis are usually associated with NMOSD and IgG-MOG cases with a worsened prognosis. Painless and chronic vision loss might occur secondary to infections and granulomatous diseases. On the other hand, optic neuritis secondary to multiple sclerosis is usually self-limited. Many of the cases of optic neuritis are characterized by being responsive to steroid therapy. However, acute vision loss was also reported in some cases. Therefore, clinicians must be knowledgeable enough to conduct the most appropriate diagnostic and management modalities to enhance the prognosis of the affected patients. Further research is needed for optimizing the treatment plan and drawing better interventions.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: Not required

REFERENCES

1. 1. Martínez-Lapiscina EH, Fraga-Pumar E, Pastor X, et al. Is the incidence of optic neuritis rising? Evidence from an epidemiological study in Barcelona (Spain), 2008-2012. J neurol. 2014;261(4):759-67.
2. 2. Woung LC, Lin CH, Tsai CY, Tsai MT, Jou JR, Chou P. Optic neuritis among National Health Insurance enrollees in Taiwan, 2000-2004. Neuroepidemiology. 2007;29(3-4):250-54.
3. 3. Rodriguez M, Siva A, Cross SA, O'Brien PC, Kurland LT. Optic neuritis: a population-based study in Olmsted County, Minnesota. Neurol. 1995;45(2):244-50.
4. 4. Soelberg K, Jarius S, Skejoe HPB. A population-based prospective study of optic neuritis. Multiple Sclerosis J. 2017;23(14):1893-1901.
5. 5. Percy AK, Nobrega FT, Kurland LT. Optic neuritis and multiple sclerosis. An epidemiologic study. Archives of ophthalmology (Chicago, Ill : 1960). 1972;87(2):135-9.
6. 6. Stunkel L, Kung NH, Wilson B, McClelland CM, Van Stavern GP. Incidence and Causes of Overdiagnosis of Optic Neuritis. JAMA ophthalmol. 2018;136(1):76-81.
7. 7. De Lott LB, Bennett JL, Costello F. The changing landscape of optic neuritis: a narrative review. J neurol. 2021.
8. 8. Beck RW, Cleary PA, Anderson MM, Jr., et al. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. The Optic Neuritis Study Group. N Eng j med. 1992;326(9):581-8.
9. 9. The clinical profile of optic neuritis. Experience of the Optic Neuritis Treatment Trial. Optic Neuritis Study Group. Archives of ophthalmology (Chicago, Ill : 1960). 1991;109(12):1673-8.
10. 10. Multiple sclerosis risk after optic neuritis: final optic neuritis treatment trial follow-up. Arch neurol. 2008;65(6):727-32.
11. 11. Kupersmith MJ, Mandel G, Anderson S, Meltzer DE, Kardon R. Baseline, one and three month changes in the peripapillary retinal nerve fiber layer in acute optic neuritis: relation to baseline vision and MRI. J neurological sci. 2011;308(1-2):117-23.
12. 12. Gabilondo I, Martínez-Lapiscina EH, Fraga-Pumar E. Dynamics of retinal injury after acute optic neuritis. Ann neurol. 2015;77(3):517-28.
13. 13. Kupersmith MJ, Gal RL, Beck RW, Xing D, Miller N. Visual function at baseline and 1 month in acute optic neuritis: predictors of visual outcome. Neurology. 2007;69(6):508-14.
14. 14. Kupersmith MJ, Alban T, Zeiffer B, Lefton D. Contrast-enhanced MRI in acute optic neuritis: relationship to visual performance. Brain: a j neurol. 2002;125(Pt 4):812-22.
15. 15. Mealy MA, Whetstone A, Orman G, Izbudak I, Calabresi PA, Levy M. Longitudinally extensive optic neuritis as an MRI biomarker distinguishes neuromyelitis optica from multiple sclerosis. J neurological sci. 2015;355(1-2):59-63.
16. 16. Ramanathan S, Prelog K, Barnes EH. Radiological differentiation of optic neuritis with myelin oligodendrocyte glycoprotein antibodies, aquaporin-4 antibodies, and multiple sclerosis. Multiple sclerosis (Houndmills, Basingstoke, England). 2016;22(4):470-82.
17. 17. Thompson AJ, Banwell BL, Barkhof F. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17(2):162-73.
18. 18. Jurynczyk M, Messina S, Woodhall MR. Clinical presentation and prognosis in MOG-antibody disease: a UK study. Brain: a J neurol. 2017;140(12):3128-38.
19. 19. Chen JJ, Flanagan EP, Jitprapaikulsan J. Myelin Oligodendrocyte Glycoprotein Antibody-Positive Optic Neuritis: Clinical Characteristics, Radiologic Clues, and Outcome. Am j ophthalmol. 2018;195:8-15.
20. 20. Hacohen Y, Wong YY, Lechner C. Disease Course and Treatment Responses in Children With Relapsing Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease. JAMA neurol. 2018;75(4):478-87.
21. 21. Wingerchuk DM, Banwell B, Bennett JL. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015;85(2):177-89.
22. 22. Kleiter I, Gahlen A, Borisow N. Neuromyelitis optica: Evaluation of 871 attacks and 1,153 treatment courses. Ann neurol. 2016;79(2):206-16.
23. 23. El-Qushayri AE, Ghozy S, Reda A, Kamel AMA, Abbas AS, Dmytriw AA. The impact of Parkinson's disease on manifestations and outcomes of Covid-19 patients: A systematic review and meta-analysis. Rev Med Virol. 2021:e2278.
24. 24. Nguyen TM, Huan VT, Reda A. Clinical features and outcomes of neonatal dengue at the Children's Hospital 1, Ho Chi Minh, Vietnam. J clin virol. 2021;138:104758.
25. 25. Dutton JJ, Burde RM, Klingele TG. Autoimmune retrobulbar optic neuritis. American journal of ophthalmology. 1982;94(1):11-7.
26. 26. Frohman L, Dellatorre K, Turbin R, Bielory L. Clinical characteristics, diagnostic criteria and therapeutic outcomes in autoimmune optic neuropathy. Bri j ophthalmol. 2009;93(12):1660-6.
27. 27. Benoilid A, Tilikete C, Collongues N. Relapsing optic neuritis: a multicentre study of 62 patients. Multiple sclerosis (Houndmills, Basingstoke, England). 2014;20(7):848-53.
28. 28. Son PT, Reda A, Viet DC. Exchange transfusion in the management of critical pertussis in young infants: a case series. Vox Sang. 2021;116(9):976-82.
29. 29. Thieu H, Bach Dat B, Nam NH. Antibiotic resistance of Helicobacter pylori infection in a children's hospital in Vietnam: prevalence and associated factors. Minerva medica. 2020;111(5):498-501.
30. 30. El-Qushayri AE, Dahy A, Reda A. A closer look to the high burden of the psychiatric disorders among health care workers (HCWs) in Egypt during COVID-19 outbreak: A meta-analysis of 3137 HCWs. Epidemiol health. 2021:e2021045.
31. 31. Kidd D, Burton B, Plant GT, Graham EM. Chronic relapsing inflammatory optic neuropathy (CRION). Brain : a j neurol. 2003;126(Pt 2):276-84.
32. 32. Petzold A, Plant GT. Chronic relapsing inflammatory optic neuropathy: a systematic review of 122 cases reported. J neurol. 2014;261(1):17-26.
33. 33. Cross SA, Salomao DR, Parisi JE. Paraneoplastic autoimmune optic neuritis with retinitis defined by CRMP-5-IgG. Ann neurol. 2003;54(1):38-50.
34. 34. Jarius S, Wandinger KP, Borowski K, Stoecker W, Wildemann B. Antibodies to CV2/CRMP5 in neuromyelitis optica-like disease: case report and review of the literature. Clin neurol neurosurg. 2012;114(4):331-5.
35. 35. Igarashi N, Sawamura H, Kaburaki T, Aihara M. Anti-Collapsing Response-Mediating Protein-5 Antibody-Positive Paraneoplastic Perioptic Neuritis without Typical Neurological Symptoms. Neuro-ophthalmol (Aeolus Press). 2017;41(1):24-9.
36. 36. Kampylafka EI, Alexopoulos H, Kosmidis ML. Incidence and prevalence of major central nervous system involvement in systemic lupus erythematosus: a 3-year prospective study of 370 patients. PloS one. 2013;8(2):e55843.
37. 37. Lin YC, Wang AG, Yen MY. Systemic lupus erythematosus-associated optic neuritis: clinical experience and literature review. Acta ophthalmologica. 2009;87(2):204-10.
38. 38. Asgari N, Jarius S, Laustrup H. Aquaporin-4-autoimmunity in patients with systemic lupus erythematosus: A predominantly population-based study. Multiple sclerosis (Houndmills, Basingstoke, England). 2018;24(3):331-9.
39. 39. Jarius S, Jacobi C, De Seze J. Frequency and syndrome specificity of antibodies to aquaporin-4 in neurological patients with rheumatic disorders. Multiple sclerosis (Houndmills, Basingstoke, England). 2011;17(9):1067-73.
40. 40. Massara A, Bonazza S, Castellino G. Central nervous system involvement in Sjögren's syndrome: unusual, but not unremarkable-clinical, serological characteristics and outcomes in a large cohort of Italian patients. Rheumatology (Oxford, England). 2010;49(8):1540-9.
41. 41. Abdelhakim A, Rasool N. Neuroretinitis: a review. Current opinion in ophthalmology. 2018;29(6):514-519.
42. 42. Purvin V, Sundaram S, Kawasaki A. Neuroretinitis: review of the literature and new observations. J neuro-ophthalmol. 2011;31(1):58-68.
43. 43. Bennett JL. Optic Neuritis. Continuum (Minneapolis, Minn). 2019;25(5):1236-64.
44. 44. Kahloun R, Abroug N, Ksiaa I. Infectious optic neuropathies: a clinical update. Eye and brain. 2015;7:59-81.
45. 45. Takazawa T, Ikeda K, Nagaoka T. Wegener granulomatosis-associated optic perineuritis. Orbit (Amsterdam, Netherlands). 2014;33(1):13-6.
46. 46. Niskopoulou M, Du Toit N. Optic neuritis as a feature of Wegener's granulomatosis. Eye (London, England). 2002;16(3):320-1.
47. 47. Koczman JJ, Rouleau J, Gaunt M, Kardon RH, Wall M, Lee AG. Neuro-ophthalmic sarcoidosis: the University of Iowa experience. Seminars ophthalmol. 2008;23(3):157-68.
48. 48. Baughman RP, Weiss KL, Golnik KC. Neuro-ophthalmic sarcoidosis. Eye and brain. 2012;4:13-25.