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00:00:19.760[Intro music] Welcome to Neurology Active Recall! This podcast is designed to combine the power of retrieval practice, an evidence-based technique for memory consolidation, with the flexibility of an audio format.
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00:00:32.240All you have to do is formulate your answer in the pause that follows each question, and with repetition, you can build confidence while driving to work, taking an evening walk, or finally doing the dishes.
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00:00:39.280As a reminder, this podcast is produced by neurology residents at the University of Colorado for educational purposes only.
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00:00:41.840It is not intended as medical advice.
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00:00:47.439The opinions expressed are the authors' and do not represent the position of the University of Colorado.
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00:01:05.920With that, let's enjoy some active studying! It doesn't take long in neurology residency before someone poses the question: what's your differential for optic neuropathy?
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00:01:12.159In this episode, we are going to take a close look at conditions that damage the optic nerve.
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00:01:28.640We'll use the VITAMINSS mnemonic, which reminds us to consider vascular, infectious, traumatic, autoimmune/ inflammatory, metabolic or toxic, iatrogenic, neoplastic, structural, and syndromic causes.
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00:01:38.480If this is a less familiar topic, you may find it helpful to review the "Optic Neuropathies" article in the April 2025 edition of Continuum first.
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00:01:41.359Additional resources are listed in the show notes.
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00:01:48.239Otherwise, let's get started! First up in the VITAMINSS mnemonic are vascular causes.
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00:01:54.079What is a good way of organizing causes of vascular or ischemic optic neuropathy?
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00:02:18.080It is helpful to divide ischemic optic neuropathies into two types: anterior ischemic optic neuropathy, which has disc swelling, and posterior ischemic optic neuropathy, no disc swelling.
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00:02:32.319Anterior ischemic optic neuropathy can be divided further into two subtypes, non- arteritic, which is often abbreviated NAION, and arteritic, most commonly giant cell arteritis.
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00:02:40.319What is the classic illness script for non- arteritic anterior ischemic optic neuropathy (NAION)?
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00:02:58.240Ninety percent of the time, NAION presents as sudden, painless vision loss, often noted upon awakening.
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00:03:10.000Sixty percent of these patients may have vascular risk factors like diabetes, hypertension, hypercholesterolemia, and obstructive sleep apnea, but recent studies have not shown a definitive link.
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00:03:15.599The fellow eye should have a small cup to disc ratio, less than 0.3.
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00:03:24.240Medications like PDE5 inhibitors may increase the risk, and recent publications have raised concern about GLP1 agonists.
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00:03:35.840What clinical features should we be asking about when considering giant cell arthritis or GCA, the most common form of arteritic anterior ischemic optic neuropathy?
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00:04:01.680Systemic symptoms like fatigue, unintentional weight loss, and myalgias (remember that connection to polymyalgia rheumatica), headaches, jaw claudication, amaurosis fugax, and scalp tenderness.
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00:04:08.639Remember, GCA is a disease of people over fifty and may occur in the absence of systemic symptoms.
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00:04:12.479Tell me about the workup and management for GCA.
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00:04:33.680Helpful features differentiating arteritic from non-arteritic anterior ischemic optic neuropathy include pallid swelling of the disc and choroidal pallor.
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00:04:36.399Vision loss is generally more severe.
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00:04:45.199Key lab features are elevated acute phase reactants like ESR and CRP, with CRP being more sensitive.
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00:04:50.800The sensitivity of ESR can be enhanced by looking for concurrent thrombocytosis.
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00:05:05.439Diagnosis is established by temporal artery biopsy, but we should not wait to start high-dose steroids, at least 60 milligrams orally, although beginning with IV methylprednisolone one gram daily may improve visual recovery.
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00:05:17.600The biopsy is still valid if performed within two weeks of starting steroids, but untreated GCA can cause vision loss in the fellow eye within days to weeks.
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00:05:32.079Longer term, steroid sparing agents include tocilizumab, an IL6 inhibitor, or sometimes methotrexate.
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00:05:36.639Now let's consider posterior ischemic optic neuropathy.
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00:05:38.879What is the classic presentation?
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00:06:00.879Posterior ischemic optic neuropathy is acute and painless, similar to NAION, but the exam will differentiate them because PION does not have disc edema since the damage is retrobulbar, distant from the optic nerve head.
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00:06:09.439It is commonly seen in cases of hypoperfusion, hypovolemia, and hypotension, such as in the setting of trauma or surgery.
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00:06:19.040Remember that GCA can present with posterior ischemic optic neuropathy and should be considered high on the differential if no inciting event occurred.
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00:06:23.199After vascular, we have infectious etiologies.
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00:06:32.399Our friendly neighborhood ophthalmologists are likely to be especially helpful for these as they tend to have associated ophthalmologic findings, but we'll cover the basics now.
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00:06:46.160Bacterial causes include:
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00:06:58.639- tuberculosis from Mycobacterium tuberculosis, which usually presents with posterior or panuveitis and often papillitis or neuroretinitis, and may be limited to the eye.
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00:07:00.009- Bartonella henselae,
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00:07:04.800- Borrelia burgdorferi, or Lyme disease,
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00:07:08.079- Treponema pallidum or syphilis,
00:07:08.079 -->
00:07:16.480- rarely Coxiella burnetii (Q fever), Rickettsia, Brucella , Whipple's, and Leptospirosis.
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00:07:19.279Viral causes include...
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00:07:31.680Viral causes include:
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00:07:37.040- VZV, where papillitis can occur during or after the varicella rash.
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00:07:43.519When occurring as a complication of zoster ophthalmicus, it is often weeks to months after the initial presentation.
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00:07:52.319- HSV, where optic nerve involvement is often with or after acute retinal necrosis,
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00:07:58.480- CMV, which typically occurs in immunocompromised patients,
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00:08:04.800- HIV, in which case it's also important to rule out opportunistic infections,
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00:08:16.240- West Nile virus, chorioretinitis is relatively common among patients with neurologic West Nile virus, typically presenting with multifocal lesions with linear clustering,
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00:08:17.680- Zika,
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00:08:19.600- Chikungunya,
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00:08:27.519- and rarely following influenza, mumps, measles, and rubella, possibly as a complication of the inflammatory response.
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00:08:30.079Fungal causes include...
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00:08:46.240- The most common fungal cause is Cryptococcus neoformans, usually in the setting of cryptococcal meningitis.
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00:09:04.879If the optic neuropathy sets on quickly, within hours to days, the mechanism is usually direct infection or ischemia from vascular inflammation, whereas gradual worsening over weeks to months may reflect damage from increased ICP, in which case optic nerve sheath fenestration can be considered.
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00:09:12.879- Candida can cause endophthalmitis, infection in the intraocular fluids in an immunocompromised patient.
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00:09:23.039- If there is a white ring arcing off the optic nerve head on fundoscopic exam, consider histoplasmosis.
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00:09:33.759- Remember that Mucormycosis and Aspergillosis can wreak havoc on the sinuses and damage the optic nerve via invasion of the orbit or ischemia from inflammation.
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00:09:42.879Parasitic causes include:
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00:09:50.480- Toxoplasma gondii, which can be considered in cases with concomitant posterior uveitis, and
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00:09:57.840- malaria, which can have a triad of retinal changes, including retinal whitening, retinovascular changes, and retinal hemorrhage.
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00:10:02.480Let's return to the most common infectious cause of neuroretinitis.
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00:10:06.000What is the classic story for ocular Bartonella?
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00:10:25.039The patient is scratched, bitten, or licked by a feral kitten, then develops fever and lymphadenopathy consistent with cat scratch fever.
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00:10:31.360About two to four weeks later, they present with unilateral vision loss and sometimes eye soreness.
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00:10:34.720What should we look for on their fundoscopic exam?
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00:10:39.519This is a bit of a trick question.
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00:10:51.039Macular star is the classic finding that should prompt consideration of infectious causes, but it usually develops about a week after the disc edema, so it may not be present on the initial exam.
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00:10:54.159What is the treatment for ocular Bartonella?
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00:11:05.759It's always good to check with ID to review local practices, but doxycycline with or without steroids can be used.
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00:11:08.960Many patients recover without intervention.
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00:11:20.000For T in the VITAMINSS mnemonic, traumatic optic neuropathy is typically abrupt in onset and associated with some form of head injury.
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00:11:23.600The trauma does not have to be severe or penetrating.
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00:11:30.879There is no treatment unless there is documented orbital canal impingement from fracture or retrobulbar hemorrhage.
00:11:30.879 -->
00:11:38.799In contrast to trauma, we'll spend more time on the A of VITAMINSS: autoimmune and inflammatory causes.
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00:11:44.480What clinical features are at the core of diagnosing optic neuritis?
00:11:54.159 -->
00:12:09.279Optic neuritis is typically monocular, subacute vision loss associated with eye pain that worsens with eye movements, reduced contrast or color vision, and relative afferent pupillary defect, or RAPD.
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00:12:24.240What does a relative afferent pupillary defect look like on exam?
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00:12:28.240We test for RAPD with the swinging flashlight test.
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00:12:31.600A light source is moved quickly from one eye to the other.
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00:12:35.600When the light is shown in the normal eye, both pupils constrict.
00:12:35.600 -->
00:12:46.559However, when the light is swung to the affected eye, there is paradoxical dilation of the pupils because the injured optic nerve cannot convey the full amount of light that eye is receiving.
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00:13:01.519Note that because the swinging flashlight test compares the pupillary response when the light is shown in one eye to the response when it is swung to the other, conditions that affect both optic nerves relatively equally will not demonstrate an RAPD.
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00:13:05.679It is a RELATIVE afferent pupillary defect after all!
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00:13:09.759What paraclinical data can help us confirm the diagnosis?
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00:13:28.240Acutely, contrast enhancement or T2 signal on MRI orbits is the most sensitive test for optic neuritis.
00:13:28.240 -->
00:13:43.919Optical coherence tomography (OCT) in the acute setting does not have specific changes linked to optic neuritis, but retinal nerve fiber layer thickening can be observed in the affected eye and may be more substantial in MOGAD optic neuritis.
00:13:43.919 -->
00:13:55.679Chronically, OCT will show thinning of the peripapillary retinal nerve fiber layer, (pRNFL), and MRI may be limited to just T2 signal change.
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00:14:01.279Disease specific antibodies may be helpful in identifying the cause of optic neuritis.
00:14:02.399 -->
00:14:06.080How would you summarize the Optic Neuritis Treatment Trial?
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00:14:50.240The optic neuritis treatment trial, published in 1992, randomized around 450 patients to three days of 1 gram IV methyl prednisolone per day, followed by 1 mg per kilogram per day oral prednisone for the remaining 11 days, versus 1 mg per kilogram per day of oral prednisone for all 14 days versus oral placebo for 14 days.
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00:14:53.519Both treatment groups then received a short taper.
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00:15:03.120The results were that visual function recovered faster in the group with IV methyl prednisolone, but there was no difference in visual acuity at six months.
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00:15:14.240Interestingly, new episodes of optic neuritis occurred roughly two times more in the low-dose oral prednisone group than in either IV methylprednisolone group or placebo.
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00:15:20.39998% of patients in this trial had MS or idiopathic optic neuritis.
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00:15:53.440When discussing inflammatory demyelinating pathologies, multiple sclerosis (MS), and idiopathic are the most common causes in the United States, but MOGAD, which stands for myelin oligodendrocyte glycoprotein associated disease, and NMOSD, whose long name is neuromyelitis optica spectrum disorder, are also important to consider.
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00:16:03.039What features could be consistent with either NMOSD or MOGAD related optic neuritis, but would be less typical for MS?
00:16:03.039 -->
00:16:18.4801) Vision 20/200 or worse at nadir.
00:16:21.360 -->
00:16:28.6392) bilateral involvement, which is seen in half of MOGAD cases and about twenty to thirty percent of NMOSD.
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00:16:41.6003) longitudinally extensive optic nerve lesions on MRI, defined as greater than half the length of the optic nerve.
00:16:41.600 -->
00:16:45.6794) absence of oligoclonal bands.
00:16:45.679 -->
00:16:56.480These markers of intrathecal IgG synthesis are found in 85% of MS optic neuritis, but about 10 to 15% of the other two types.
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00:17:02.879What additional features are more classic for NMOSD, specifically?
00:17:12.319 -->
00:17:16.000- Chiasmal or optic tract involvement
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00:17:19.920- positive aquaporin-4 antibody
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00:17:23.839- and poor recovery with chronic visual acuity worse than 20/200.
00:17:26.400 -->
00:17:30.240What additional features could point towards MOGAD, specifically?
00:17:38.480 -->
00:17:46.0001) optic disc edema correlating to a thickened RNFL if OCT is performed acutely.
00:17:46.880 -->
00:18:07.4402) perineural enhancement that may help distinguish MOGAD from MS and NMOSD, although it can also be seen in syphilis, sarcoidosis, ANCA vasculitis, or even GCA.
00:18:08.799 -->
00:18:22.0003) while both NMOSD and MOGAD can have severe visual acuity loss initially, MOGAD tends to have an excellent response to steroids, and other brain lesions may actually resolve on subsequent MRIs.
00:18:22.960 -->
00:18:53.519It is important to note that a low positive MOG titer must be confirmed with a negative aquaporin- 4 antibody and another supporting feature like bilateral clinical presentation, longitudinal optic nerve lesion, perineuritis, or prominent disc edema, or by a classic finding in the brain or spine.
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00:19:01.359What is the differential for other, less common causes of optic neuritis?
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00:19:55.839Systemic inflammatory diseases like sarcoidosis, lupus, and Sjogren's, ANCA vasculitis like granulomatosis with polyangiitis, abbreviated GPA, or microscopic polyangiitis, abbreviated MPA, or antibody-mediated conditions like GFAP, also known as glial fibrillary acidic protein, or CRMP 5, spelled CRMP5, also known as collapsin response mediator protein five.
00:19:58.720 -->
00:20:02.319What associated features should make us consider GPA?
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00:20:23.119GPA can affect the upper respiratory tract - for instance, sinusitis - as well as the lung or kidneys, and can cause mononeuritis multiplex.
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00:20:35.039Anti-GFAP meningoencephalomyelitis can rarely cause bilateral disc edema, mimicking papilledema, usually with preserved visual acuity.
00:20:35.039 -->
00:20:50.400The key imaging finding is linear perivascular contrast enhancement extending radially, meaning at a right angle, from the ventricles.
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00:21:03.359Detection of CRMP five antibody should prompt a search for small cell lung cancer or thymoma.
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00:21:05.920Excellent.
00:21:05.920 -->
00:21:12.319What are some toxic metabolic causes of optic neuropathy as we move into the M of VITAMINSS?
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00:21:28.400- Methanol or ethylene glycol poisoning,
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00:21:35.279- B12, folate, and thiamine deficiencies, all of which can occur from chronic alcohol use,
00:21:35.279 -->
00:21:38.319- copper deficiency or zinc excess,
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00:21:50.960- or medications like ethambutol, amiodarone, or linezolid, particularly with long term use, can all damage the optic nerve.
00:21:50.960 -->
00:22:06.720In addition to the above iatrogenic causes, radiation - particularly of the nasopharynx, or orbital or middle cranial fossa (for example, for meningiomas) - can cause optic neuropathy months to years later.
00:22:06.720 -->
00:22:12.319We'll turn our attention towards neoplastic causes now.
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00:22:23.920Acknowledging that the presentation can vary based on the optic chiasm's position relative to the sella, what are two visual field defects that could point towards a compressive pituitary lesion?
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00:22:43.759- Bitemporal hemianopsia, because fibers transmitting temporal field visual input cross at the chiasm, whereas fibers transmitting the nasal field do not cross.
00:22:43.759 -->
00:22:49.759Therefore, lesions compressing the anterior chiasm typically impact the temporal fields.
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00:23:10.480- Junctional scotoma, which refers to a central scotoma with decreased visual acuity in the ipsilateral eye, coupled with a superior temporal visual field defect in the contralateral eye.
00:23:12.000 -->
00:23:18.079In addition to compressive pituitary lesions, what other neoplasms can impact the optic nerve?
00:23:29.359 -->
00:23:32.799Neoplasms that directly affect the nerve include:
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00:23:34.7201) optic glioma.
00:23:34.720 -->
00:23:47.599About 90% of optic gliomas occur in children, where they are often pilocytic astrocytomas and can be associated with neurofibromatosis type one.
00:23:47.599 -->
00:23:53.119However, adults with optic glioma may have the malignant form, glioblastoma.
00:23:53.759 -->
00:23:59.5992) infiltration by leukemia, lymphoma, or histiocytosis.
00:24:00.240 -->
00:24:04.319Neoplasms that compress the nerve include:
00:24:04.319 -->
00:24:17.5991) optic nerve sheath meningiomas, which typically present with chronic progressive vision loss and often require treatment with debulking or radiation therapy to prevent progressive vision loss.
00:24:18.559 -->
00:24:21.2002) orbital metastases.
00:24:21.200 -->
00:24:51.680Other structural causes can include dysthyroid optic neuropathy from Graves' thyroid eye disease - the enlarged muscles can compress the nerve, or more rarely, the proptosis can stretch it - as well as inflammatory conditions like IgG4 disease and idiopathic orbital inflammatory disease.
00:24:51.680 -->
00:24:56.079For the last S, we'll discuss genetic syndromes.
00:24:56.079 -->
00:25:00.720What would be the classic story for Leber Hereditary Optic Neuropathy?
00:25:00.720 -->
00:25:23.440The classic story for Leber Hereditary Optic Neuropathy would be a young man with subacute, painless vision loss in one eye, followed by a similar course in the fellow eye within about two months.
00:25:23.440 -->
00:25:37.519The pathophysiology is generally mutations in mitochondrial DNA affecting complex one of the electron transport chain.
00:25:37.519 -->
00:26:47.119Now that we've toured the differential of optic neuropathy in detail, let's put it all together and rehearse our answer to "What's your differential for optic neuropathy?"
00:26:47.119 -->
00:26:49.599First, vascular causes.
00:26:49.599 -->
00:27:10.799These include non-arteritic anterior ischemic optic neuropathy (NAION), and arteritic anterior ischemic optic neuropathy, most often caused by giant cell arthritis, as well as posterior ischemic optic neuropathy.
00:27:11.440 -->
00:27:24.799Infectious causes include bacterial causes like tuberculosis, Bartonella henselae (cat scratch fever), Lyme disease, and syphilis.
00:27:26.079 -->
00:27:40.960Viral causes include herpes viruses, West Nile virus, HIV, Zika, and Chikungunya.
00:27:40.960 -->
00:27:57.680Fungal causes include Cryptococcus, Histoplasma, Candida, or Mucormycosis or Aspergillosis spreading from the sinuses.
00:27:58.559 -->
00:28:00.640Trauma is another cause.
00:28:01.039 -->
00:28:43.839For autoimmune/ inflammatory causes, we often think of MS, NMOSD, and MOGAD, the latter two of which we should consider when vision is worse than 20/200 nadir, both optic nerves are involved, or there is longitudinally extensive optic neuritis, oligoclonal bands are absent, or there are features suggestive of NMOSD, like chiasmal or optic tract involvement, or features of MOGAD like optic disc edema or perineural enhancement.
00:28:43.839 -->
00:29:01.759Rarer causes include sarcoid, lupus, Sjogren's, ANCA vasculitis, GFAP, or CRMP5.
00:29:03.440 -->
00:29:28.079Metabolic or toxic causes include B12, folate, or thiamine deficiency, methanol or ethylene glycol poisoning, copper deficiency, or medications like ethambutol, amiodarone, or linezolid.
00:29:29.359 -->
00:29:35.920Other iatrogenic causes include nasopharyngeal or cranial radiation.
00:29:37.519 -->
00:29:50.079Neoplastic causes include compression by pituitary masses, optic nerve sheath meningiomas or orbital mets.
00:29:50.079 -->
00:29:59.519Neoplasms directly affecting the nerve include optic glioma or infiltration by lymphoma, leukemia, or histiocytosis.
00:30:00.720 -->
00:30:27.200Other structural causes include thyroid eye disease or idiopathic orbital inflammatory disease, and a genetic syndrome would be Leber Hereditary Optic Neuropathy, which presents subacutely with sequential involvement of the two eyes.
00:30:27.200 -->
00:30:30.079With that, I would like to give a special thanks to Dr.
00:30:30.079 -->
00:30:31.519Jeffrey Bennett and Dr.
00:30:31.519 -->
00:30:35.440Elizabeth Matthews for their guidance with this episode, and to Dr.
00:30:35.440 -->
00:30:38.000Edith Sigler for our theme song.
00:30:38.000 -->
00:30:45.359And of course, thank YOU for joining us! If you would like to enjoy more active studying, please subscribe to our show.
00:30:45.359 -->
00:30:50.400And if there is a way we could be more helpful, please let us know at neurologyactiverecall@gmail.com.
00:30:52.400 -->
00:30:53.440Thank you! [Outro music]
