This article is the second in a two-part series examining the optic nerve head (ONH). The first instalment focused on congenital disorders of the optic nerve while this article will feature acquired anomalies presented using a series of case studies.
IntroductionAcquired optic nerve abnormalities present with a range of characteristic features requiring the practitioner to consider various differential diagnoses, to take appropriate management steps, and to understand potential systemic implications. This article outlines a series of acquired conditions affecting the optic nerve.
Optic neuritisA 28-year-old man presented to clinic with cloudy vision in his right eye for the past two days. He reported that his eye was sensitive to touch along the upper eyelid and that he felt mild pressure on extreme gaze.
He had an unremarkable ocular and general medical history other than a melanoma removed from his arm when he was 17 years old.
His best-corrected vision was 6/24 in the right eye (pinhole no improvement) and 6/6 in the left eye. He had a right relative afferent pupillary defect (RAPD). Confrontation fields and extraocular muscle movements (EOMs) were full but with pain reported on eye movements. Colour vision was notably reduced using Ishihara plates in the right eye and was normal in the left eye. Eye pressure and anterior segment findings were normal as were posterior pole and peripheral retinal findings. The left optic nerve head (ONH) was normal, while the right ONH showed mild temporal pallor with slightly indistinct margins superiorly and nasally; cupping was graded at 0.3h/0.3v in both eyes (see Figure 1: Optomap images of patient presenting with optic neuritis in the right eye).
The patient was diagnosed with optic neuritis in the right eye and was referred to a neurologist. He underwent a MRI scan three days later, which showed early signs of multiple sclerosis (MS).
Optic neuritis is an inflammation of the optic nerve which may be classified as: papillitis, which is associated with disc swelling and peripapillary flame-shaped haemorrhages, and located anterior to the disc;1 or retrobulbar which is posterior without disc swelling and is more common.2 In acute retrobulbar cases the phrase ‘the doctor sees nothing and the patient sees nothing’ is sometimes true when optic nerve damage is so recent that sufficient time has not passed for atrophic changes to occur. Optic neuritis is most often caused by demyelination but can also be related to vasculitis, infection, or autoimmune disease.1 Demyelinative optic neuritis is most often seen in 15 to 45-year-old females and is frequently associated with MS.2 About 20% of MS patients initially present with optic neuritis as their first manifestation of the disease.2 In children, optic neuritis is more commonly papillitis,1 which is bilateral and postviral.2
Patients present typically as the case study described earlier with unilateral vision loss occurring over hours to days with vision ranging from 6/6 to no light perception, pain on eye movement, diminished sense of brightness which may be assessed with the simple red-cap test,2 and dyschromatopsia (usually blue-yellow defects later changing to red-green).3 Additional signs may include a visual field defect (most commonly central or paracentral scotoma), optic disc swelling (in 35% of cases), and mild vitritis.2 Patients may experience altered perception of moving objects, known as Pulfrich’s phenomenon or worsening of symptoms with increased body temperature such as in exercise, known as Uhthoff’s sign.1 OCT imaging, which is becoming standard in optic neuritis diagnosis and management will show initial thickening during the acute phase followed by thinning and loss of axons in later phases,4 with most thinning by three to six months and then stabilisation around seven to 12 months (see Figure 2: A patient several years post optic neuritis with temporal disc pallor and atrophy).5 Interestingly, the seemingly unaffected eye also shows subclinical RNFL loss on OCT imaging.5 Additional technologies such as multifocal ERG and VEP can aid in diagnosis and management but are not currently mainstays in standard of care.5,6
The Optic neuritis treatment trial (ONTT) was a large well-designed study primarily investigating the natural course and management of optic neuritis. It showed that a patient with optic neuritis and positive MRI for MS should be given intravenous (IV) steroids in order to hasten visual recovery although final visual outcomes were not significantly improved compared to no treatment. Oral steroids should be avoided as they lead to an increased risk of recurrent optic neuritis. Additionally, the probability of developing MS by 15 years after an acute optic neuritis episode was 50% and strongly associated with the presence of brain MRI lesions at the time of the initial episode. If no MRI lesions were present, then lower risk was also associated with male gender, optic disc swelling and atypical presentation of optic neuritis including peripapillary haemorrhages and vision reduced to no light perception.3
The Controlled high-risk Avonex multiple sclerosis (CHAMPS) study looked at patients following their first acute optic neuritis episode with a positive lesion on brain MRI. Those treated with interferon beta 1-A (Avonex) in addition to IV steroids had a 44% reduction in three-year probability of developing clinically definite MS;7 the results extended into the fifth year.8
In patients with previously diagnosed MS, then observation is recommended every four to six weeks after presentation and then every three to six months thereafter.1 In patients with demyelinative optic neuritis, prognosis is good for visual recovery and is dependent on severity of initial visual loss; about 70% of patients recover 6/6 vision.2 Patients may have permanent colour vision changes, contrast sensitivity deficits, and continued experience of Uhthoff’s sign.4 Novel investigative techniques such as neuroimmunology and treatments such as remyelination therapies are currently being investigated for MS and broader central nervous system disorders.6
Non-arteritic ischaemic optic neuropathy (NAION)/Arteritic ischaemic optic neuropathy (AION)A 61-year-old male presented to the hospital eye clinic with complaints of reduced vision and reduced field of view in his right eye. He reported that the vision loss occurred the day after an international flight from Malaysia to North Carolina, United States. He was a well-controlled type II diabetic without significant other ocular or general medical history.
His best-corrected visual acuity was 6/38 in the right eye (pinhole no improvement) and 6/7.5 in the left eye.
He had a right RAPD and a superior altitudinal visual field defect in the right eye (see Figure 3: Right superior altitudinal defect). EOMs were full and anterior segment findings including intraocular pressure were normal in both eyes. The right disc was swollen and chalky white with an indiscernible C/D ratio. The left disc appeared normal with a 0.1 C/D ratio. Upon further questioning, he was not experiencing jaw pain or scalp tenderness.
As the patient was seen in the hospital setting, he was referred directly for blood tests, which were negative for elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels. He was diagnosed with presumed non-arteritic ischaemic optic neuropathy and was seen in the adjacent ophthalmology clinic. Although not cited in the literature, it was proposed by the medical team that his long-distance flight was associated with venous stasis (as well as possible dehydration), which may have played a role in the pathogenesis of his episode.
Anterior ischaemic optic neuropathy is defined as an infarction of the optic nerve secondary to occlusion of the posterior circulation just behind the lamina cribosa.2 It is divided into two categories: arteritic (10% of cases) and non-arteritic (90% of cases).9 Posterior ischaemic optic neuropathy (PION) is similarly categorically divided and involves the posterior part of the nerve.9
AION occurs in the setting of giant cell arteritis (GCA). It usually presents in patients >55 years old,2 with 70 years old as the median affected age,10 and more commonly in females.10 The fellow eye is involved in 75% of cases within days to two weeks without treatment.2 Symptoms include acute, unilateral, painless and profound visual loss (around 6/60 or worse) and dyschromatopsia.1 AION is frequently associated with scalp tenderness and jaw claudication, specifically pain when chewing.10 Additional systemic symptoms may include headache, fever, malaise, weight loss, amaurosis fugax, and joint pain.2 Signs may include a swollen, tender temporal artery (located on either side of the forehead and easily examined with palpation), RAPD, pale disc swelling, cotton-wool spots, flame-shaped disc haemorrhages, central retinal artery occlusion, and central or altitudinal visual field defects.2 GCA involves granulomatous inflammation of large and medium sized arteries and AION occurs from an inflammatory thrombosis of the short posterior ciliary artery.10
NAION is most often spontaneous without a specific identifying precipitating factor but is associated with several systemic diseases: hypertension, diabetes mellitus, ischaemic heart disease, hypercholesterolaemia, smoking, and obstructive sleep apnoea.2,11 It usually occurs in middle-aged patients,2 from 40 to 60 years old.1 It is characterised by sudden, painless vision loss by a moderate degree, initially unilateral, but may become bilateral.1 Signs include RAPD, pale disc swelling, flame- shaped haemorrhages, dyschromatopsia, and altitudinal or central visual field defect.1 The unaffected eye often has a ‘disc-at-risk’ appearance with a small cup-to-disc ratio.12 The pathogenesis of NAION is highly complex and is likely to be associated with small vessel disease involving the short posterior ciliary arteries with resultant hypoperfusion and infarction.12 Often visual symptoms are noted within two hours of waking indicating a nocturnal hypotensive event.9
The optic disc changes seen in both AION and NAION begin as a swollen, oedematous, but not hyperaemic, followed by pallor or atrophy after six to eight weeks.1,2 The changes can be differentiated from glaucoma based on the often segmental nature,1 and the lack of enlarged peripapillary atrophy.13
Emergent lab testing includes ESR and CRP levels which will be elevated in AION, but usually not in NAION.1,2 A further temporal artery biopsy can confirm the diagnosis of AION. Fluorescein angiography12 and OCT imaging can be of further usefulness.14
Some controversy surrounds treatment of AION and NAION. Systemic steroids are typically started intravenously for AION for three days and then alternated to oral prednisone with a very slow taper when ESR and CRP levels are normal.1 Daily aspirin has been recommended in NAION.2 However, some refute the benefit of aspirin and recommend instead corticosteroid therapy during the initial stages.9
About 10% to 30% of patients with NAION will have progressively worse VA and about 42% will gain visual acuity improvements over three to six months but no visual improvement is seen after six months.1,2,9 In the case of NAION, the risk of another episode in the same eye is 5% while the risk in the contralateral eye is 15% within five years.12 The patient described in the case study has not had an episode in the left eye and his acuity improved moderately, however his activities of daily living were adversely affected by the persistent visual field loss for which he is in low vision rehabilitation training.
Toxic optic neuropathy
An 80-year-old white male presented to clinic with complaints of decreasing vision in both eyes over the past several weeks. He was a longstanding glaucoma suspect and had successful cataract extraction 10 years prior.
He was being treated with ethambutol for a tuberculosis infection discovered about six months previously. Best-corrected visual acuity was 6/120 in both eyes, pinhole no improvement, which was reduced from previous recorded acuities of 6/12 in each eye. He had sluggish pupil reactions without RAPD along with reduced colour vision using Ishihara plates in each eye individually. Matrix visual field screening showed central scotomas along with a few points missed peripherally in both eyes. Ocular motility was full without pain. External exam and intraocular pressures were unremarkable. Posterior pole evaluation showed C/D ratios of 0.8h/0.7v in both eyes with questionable temporal pallor. The peripheral retina on dilation was normal.
Although being a glaucoma suspect was somewhat confounding, the new signs and symptoms in the presence of ethambutol treatment pointed to toxic optic neuropathy. He was eventually referred back to the internist and was given an alternative tuberculosis medication. Visual acuity improved to 6/18 in both eyes.
Toxic optic neuropathy is characterised by painless, progressive, and often bilateral loss of visual acuity to around 6/18 to 6/120.1 Patients often have reduced colour vision initially reported as a loss of brightness with certain colours, namely red.15 Visual field defects are common and show a central or cecocentral scotoma.1,2 A RAPD is not usually present because of the bilateral and symmetric nature of the disease.16,17 As in optic neuritis, the disc usually appears normal initially although acute poisoning may be associated with oedema and hyperaemia.17 Disc haemorrhages may be present17 and are often flame-shaped.15 Finally, papillomacular bundle loss and optic atrophy occurs usually beginning temporally17 and then extending to complete disc atrophy as the extent of the nerve fibre damage worsens.15
Inciting medications are often one of the following: chloramphenicol, ethambutol, isoniazid, digitalis, chloroquine, streptomycin, chlorpropamide, ethchlorvynol, disulfiram, methanol, carbondioxide, amiodaroneandmetals such as lead.1,17 Patients present similarly when severely malnourished as in the case of vitamin B deficiencies such as in thiamine (vitamin B1) deficiency and in pernicious anaemia (vitamin B12 malabsorption).16 Deficiencies in folic acid and proteins with sulphur-containing amino acids and severe tobacco/alcohol abuse are also associated with toxic optic neuropathy.17 The proposed pathophysiology includes mitochondrial injury and imbalance of intracellular and extracellular free radical homeostasis, 17 combined with interruption of normal retinal cell synapses.15
A referral for lab testing is essential and includes complete blood count (CBC), blood chemistries, urinalysis and serum lead levels. MRI is also essential to rule out intracranial processes or mass lesions.2 Further testing with OCT, VEP, and ERGs may be useful in ruling out other optic nerve disorders.17
Treatment involves removing the causative agent and correcting any deficiencies or malabsorption.2 Cessation of smoking and alcohol use is recommended for all patients along with general nutritional improvement.15 Oral replacement of thiamine, folic acid and cyanocobalamin may be particularly beneficial.15
Follow-up exams should be performed every four to six weeks initially17 and then every six to twelve months.1 The prognosis depends on the dosage and duration of exposure to the toxic substance.17 Usually after discontinuation of the offending agent and/or treatment with vitamin supplementation, then vision improves over several weeks, 17 to months.18 However, once atrophy has occurred then there is poor chance of visual recovery.2 Even where visual acuity improves, deficits often remain in visual fields, colour vision, and contrast sensitivity.18
Interestingly, as illustrated in the case study, it has been reported that up to 6% of those taking ethambutol experience toxic optic neuropathy with signs and symptoms appearing between four and 12 months after initiating treatment.17 Additionally, those taking antiviral medication, for example HIV-positive patients, in addition to ethambutol may be at even higher risk of optic neuropathy.18 Therefore, when prescribed the commonly causative drugs a patient should be educated about symptoms of toxic optic neuropathy and should undergo regular eye examinations.
The intricate formation, detailed structure, and dynamic function of the optic nerve lend itself to many congenital and acquired optic nerve anomalies. A proper understanding of what constitutes a physiologically normal ONH in addition to careful investigation on every patient is paramount for effective differential diagnosis of various conditions of congenital and acquired origin in benign and progressive forms.
About the author
Dr Kate Lanier is a clinical instructor at Anglia Ruskin University and author for KMK Continuing Education. She completed a primary care/ocular disease residency at the W.G. Bill Hefner VA Medical Center hospital in the US and worked in a medical-model private practice in North Carolina.
- Ehlers JP, Shah CP (2008) The Wills Eye Manual. Lippincott Williams and Wilkins, Baltimore, USA
- Kaiser PK, Friedman NJ, Pineda R (2004) The Massachusetts Eye and Ear Infirmary Illustrated Manual of Ophthalmology. Saunders, Philadelphia, USA
- Beck R and Optic Neuritis Study Group (2008) Multiple sclerosis risk after optic neuritis: final optic neuritis treatment trial follow-up. Arch Neurol. Jun;65(6):727-32
- Petzold A, Watties MP, Costello F, et al (2014) The investigation of acute optic neuritis: a review and proposed protocol. Nat Rev Neurol. Aug;10(8):447-58
- Kemenyova P, Turcani P, Sutovsky S, et al (2014) Optical coherence tomography and its use in optical neuritis and multiple sclerosis. Bratisl Lek Listy. 115(11):723-9
- Bennett JL, Nickerson M, Costello F, et al (2015) Re-evaluating the treatment of acute optic neuritis. J Neurol Neurosurg Psychiatry. Jul;86(7):799-808
- Galetta SL (2001) The controlled high risk Avonex multiple sclerosis trial (CHAMPS Study). J Neuroophthalmol. Dec;21(4):292-5
- Kinkel RP, Kollman C, and CHAMPIONS Study Group (2006) IM interferon beta-1a delays definite multiple sclerosis 5 years after a first demyelinating event. Neurology. Mar 14;66(5):678-84
- Hayreh SS (2013) Ischemic optic neuropathies - where are we now? Graefes Arch Clin Exp Ophthalmol. Aug;251(8):1873-84
- Chacko JG, Chacko JA, Salter MW (2015) Review of Giant cell arteritis. Saudi J Ophthalmol. Jan-Mar;29(1):48-52
- Fraser CL (2014) Obstructive sleep apnea and optic neuropathy: is there a link? Curr Neurol Neurosci Rep. Aug;14(8):465
- Rucker JC, Biousse V, Newman NJ (2015) Ischemic Optic Neuropathies. N Engl J Med. Jun 18;372(25):2428-36
- Jonas JB. Clinical implications of peripapillary atrophy in glaucoma (2005) Current Opinion in Ophthalmology. 16:84-8
- Rebolleda G, Diez-Alvarez L, Casado A, et al (2015) OCT: New perspectives in neuro-ophthalmology. Saudi J Ophthalmol. Jan-Mar;29(1):9-25
- Chiotoroiu SM, Noaghi M, Stefaniu GI, et al (2014) Tobacco-alcohol optic neuropathy--clinical challenges in diagnosis. J Med Life. Oct-Dec;7(4):472-6
- Ramkumar HL, Savino PJ (2014) Toxic optic neuropathy: an unusual cause. Indian J Ophthalmol. Oct;62(10):1036-9
- Grzybowski A, Zülsdorff M, Wilhelm H, et al (2014) Toxic optic neuropathies: an updated review. Acta Ophthalmol. Aug 93(5):402-10
- Mustak H, Rogers G, Cook C (2013) Ethambutol induced toxic optic neuropathy in HIV positive patients. Int J Ophthalmol. Aug 18;6(4):542-5