Transcript

PLEASE NOTE: While an effort has been made to correct errors in this AI-generated transcript, some mistakes may have been missed by the non-clinician moderator. This transcript should be taken merely as supporting material to the podcast and not as an authoritative review. 

MIC CAVAZZINI:          Welcome to Pomegranate Case Reports. Another podcast format generated by members of the Royal Australasian College of Physicians. I’m Mic Cavazzini but for this episode I’m going to hand the reigns over to Dr Stephen Bacchi. He’s a neurology registrar at the Lyell McEwin Hospital and a Fullbright scholar, and I recruited him to the podcast editorial group after he peppered me with lots of ideas and feedback last year.  

It was Stephen’s suggestion to present some case reports that could be educational for trainees, in particular. Today’s example comes from Royal Adelaide Hospital and you’ll find a link in the show notes to the full story at the Journal of Neuro-ophthalmology. But perhaps you can test yourself first as you listen to two of its authors drip feed findings from the patient history and examination. I hope you learn something, and maybe even feel inspired to submit a case report yourself in future. Over to Dr Bacchi.

STEPHEN BACCHI:       Thanks for joining us. So with me today, I've got Dr Sumu Simon, who's a Fellow of the Royal Australian and New Zealand College of Ophthalmologists. She completed her Masters in Ophthalmology from Christian Medical College, Vellore, India. She became a Fellow of RANZCO in 2012 and she’s is a general ophthalmologist, with special interests in neuro-ophthalmology, adult strabismus, adult squint surgery, medical retina, cataract and glaucoma. And from a physician side of things, I've got Dr Brandon Stretton, who's a basic physician trainee with an interest in perioperative medicine and evidence-based medicine on the whole. Thank you very much for joining us.

SUMU SIMON:            Thank you for having us, Stephen.

BRANDON STRETTON:           Thanks for having us.

STEPHEN BACCHI:       So today, we'll be going through a case and going through some questions that are relevant to our general audience and also trainees. So, to start off with, we have a 68 year old man. He’s presented to the emergency department. He’s got a history of type 2 diabetes mellitus, and he's presented with sudden onset monocular vision loss in the right eye for several hours. Dr Simon, could you please talk us through the types of differentials you've been concerning at this stage?

SUMU SIMON: So we are dealing here with acute onset unilateral visual loss in a 68 year old gentleman with known vascular risk factors. So, I would take a more detailed history in order to know more about the visual loss because that is quite helpful in determining the underlying cause for the vision loss. So, I want to know whether the unilateral nature of the vision loss was confirmed by occluding one eye at a time.  I want to know more about the severity of visual loss and whether the visual loss is stable, progressive or improving.  I also want to find out whether the vision loss was associated with pain or not. It is important to ask the patient whether the visual loss is central. So, central vision loss could be seen in neuropathy or macular related vision loss. Whereas if it’s more generalised it’s likely to be related to an optic nerve or retinal problem.

You also want to know whether it’s affecting just a portion of the field of vision. So, I also want to know about other associated ocular symptoms like transient monocular vision loss, redness, flashing lights and double vision. I would enquire about neurologic and systemic symptoms including headache, jaw claudication and scalp tenderness. It is also important to ask for a history of trauma and to go through the medical diagnosis, past medical history and medications as all this could provide valuable clues to the underlying aetiology.

So our patient has presented with unilateral and sudden vision loss – so the localisation of vision loss is to the prechiasmal region – and it could be anywhere between the cornea and the prechiasmal optic nerve.  Considering the patients age, and the fact that he has known vasculopathic risk factors, the differential diagnosis for sudden vision loss will include 1. Optic neuropathy 2. Vitreo-retinal causes- vitreous haemorrhage , retinal detachment, retinal vascular occlusions or wet age-related macular degeneration  3. Uveitis and Corneal oedema can also present with sudden visual loss on this age group/

STEPHEN BACCHI:       Thank you. So, how would your approach to painless vision loss defer to vision loss with pain?

SUMU SIMON:            So, it is important to find out whether the patient had a painless or painful vision loss as this helps me to narrow the differential diagnosis. The vision loss is painless in retinal vascular occlusion, non-arteritic ischaemic optic neuropathy, compressive optic neuropathy as well as in a number vitreo-retinal conditions such as vitreous haemorrhage, wet macular degeneration and retinal detachment.

Vision loss associated with pain, on the other hand, is most often indicative of an underlying inflammatory cause but can also be due to an infectious or infiltrative  cause. Painful visual loss can also be due to or due to raised intraocular pressure for example in a patient with acute angle closure glaucoma. Be also aware that pain on eye movement associated with visual loss is most often seen in optic neuritis-related vision loss.

STEPHEN BACCHI:       And Dr Simon, how about if there were an altitudinal visual field loss?

SUMU SIMON:            So altitudinal field loss tells is that the patient is missing either the superior or inferior half of the peripheral field of vision. The presence of an altitudinal field loss does not point to a specific diagnosis. It can be seen in patients with optic neuropathy. But it can also be seen in patients with retinal vascular occlusion for example a hemiretinal arterial or hemiretinal vein occlusion. Sometimes patients with retinal detachment can present as an altitudinal visual field loss as well.

STEPHEN BACCHI:       Well that’s very helpful, that gives us a framework to approach this patient. With additional history-taking, the patient discloses how the night before their presentation they, in fact, had preceding ipsilateral, ten minutes of vision loss. So, the same eye had ten minutes of visual loss the night before. So Dr Simon, outline how that affects your thought processes and how you describe this phenomenon? And then Brendon, I’d be interested in your thoughts as well.

SUMU SIMON:            So the history of proceeding ipsilateral monocular vision loss lasting for ten minutes is very important. This visual symptom is suggestive of amaurosis fugax. Amaurosis fugax is transient monocular vision loss that occurs secondary to ischaemia in the retina, choroid or the optic nerve. It is a form of transient ischaemic attack, so, you can compare it to the TIA-equivalent affecting the eye and usually lasts from a few seconds to 30 minutes, and the visual loss is followed by a full visual recovery. Patients often describe this as blacking out of vision or a grey curtain that progresses from the periphery and moves towards the centre of the vision. Amaurosis fugax is a presenting symptom in 7 to 18 percent of patients with visual loss due to giant cell arteritis. So it is important to be aware that amaurosis fugax can be the presenting symptom of GCA and that it is an important predictor of permanent and visual loss in patients with the giant cell arteritis.

So, amaurosis fugax can be due to ocular ischemia from a significant carotid artery stenosis. It can be due to transient disruption of ocular circulation due to emboli from an artheromatous plaque in the internal carotid artery. But it can also be due to cardiac causes like atrial fibrillation, or from plaques adherent to the valvular heart disorders. Patients with amaurosis fugax need urgent evaluation as they are at high risk of irreversible visual loss, cerebral vascular accidents and myocardial infarction. If you do an examination in a patient with amaurosis fugax, a lot of the clinical findings are often unremarkable. Patients with the symptom need prompt blood tests for inflammatory markers and assessment of vasculopathic risk factors. In addition to blood tests, urgent carotid ultrasound, brain scan, ECG and cardiac echo should also be organized.

BRANDON STRETTON:           I don't have much to add to that. That was very comprehensive. I would just use the term transient monocular vision loss, however. The term amaurosis fugax is one that commonly gets thrown around in these settings. Amaurosis is actually the Greek word meaning to darken to obscure and fugax translating to transient or fleeting, if I recall correctly. So the term is often used to describe or depict episodes of sudden vision loss that are temporary and effect one eye. And the implication when using that term is that it's related to an interruption in the blood flow in the retina. So, bearing in mind that the blood flow is supplied by ophthalmic artery, which in turn is a branch of the internal carotid, pertinent considerations for someone with amaurosis fugax would be an atherosclerotic embolus as Dr Simon said, from the ipsilateral carotid artery stenosis or something a bit further down like a cardioembolism which could be caused by atrial fibrillation or other valvulopathies or maybe even a mural thrombus. So bearing that in mind, and particularly noting that Dr Simon said we consider these as TIA mimic, this is something we tend to consider as a harbringer for a stroke. It’s something we take very seriously with the extensive workup formerly mentioned. And other causes of retinal ischaemia being something to consider to be like a vasculitis, particularly a GCA.

STEPHEN BACCHI:       Great, thanks. So on the whole this is worrying; increases our concern thinking about ischaemia, thinking about carotid stenosis, cardioembolism, and giant cell arteritis are all things are thinking about. So now additional information; the patient discloses some more symptoms. They describe that they've had systemic symptoms of neck pain, temporal headache and tenderness for two weeks before presentation.

Their best corrected visual acuity is found to be hand movements in the right eye and six on six in the left eye. Examination shows a RAPD in the right eye with associated dyschromatopsia and a central retinal artery occlusion or CRAO. So Dr Simon, for the sake of discussion and learning, could you please explain to us what a RAPD is?

SUMU SIMON:            The systemic symptoms are highly suggestive. I am concerned that this could be a giant cell arteritis-related central retinal artery occlusion, at this stage. So relative afferent pupillary defect is a critical test in a patient who presents with vision loss. Not only acute vision loss but also someone who presents with chronic visual loss. It is important to remember that normal individuals have bilateral and equal innervation of pupils. RAPD is helpful in eliciting a defect in the pupil pathway on the afferent side. RAPD is relative to the fellow eye. It is assessed, as you all know, by the swinging flashlight test. The normal pupillary response is characterised by equal constriction of pupils in both eyes when the light stimulus is applied to each eye individually with no dilation when the light swings from one eye to the other. When the patient has an RAPD, pupil constricts in both eyes when light shines into the normal eye but there is dilation of pupils in both eyes when the light stimulus is rapidly transferred from the normal eye to the pathologic eye. So RAPD is a difference in pupillary light reaction between the two eyes and gives you objective evidence of afferent pupillary dysfunction.

RAPD is most often seen in unilateral or asymmetric bilateral lesions affecting the retina and the prechiasmal optic nerve. But they can also be seen in lesions affecting the visual pathway in front of lateral geniculate body. If you find an RAPD, what you know is that this is not coming from other ocular conditions, say, for example cataracts, or corneal oedema. RAPD is also useful in localising the site of visual loss in patients with unilateral vision loss. For example, in our patient this helps me to localise the site of visual loss as being either in retina or prechiasmal optic nerve.

STEPHEN BACCHI:       Thank you, Dr Simon. That really helps me, because from a neurology perspective we’re all about localizing the lesion and the optic nerve is similar in many ways. So, the RAPD in this instance is helping us localize the lesion to either involving the retina or the prechiasmal optic nerve. We know that's what we're dealing with here and the question is, what's the aetiology? And we've got some additional information that history that's pointing us in particular direction. So now, they do an optical coherence tomography, or an OCT, and fundus fluorescein angiogram, abbreviated to FFA, which demonstrate severely decreased arterial filling and non-distinct retinal layers in both eyes. Their initial blood tests return in the emergency department setting and their CRP, or C reactive protein, was 29.8 and ESR, erythrocyte sedimentation rate, was 59. And they have platelets of 362, on presentation. Dr Simon, I have to say some things in ophthalmology always make me pause and think and then look it up. And some of these tests are among those categories. Could you please explain what an OCT and FFA is for a generalist audience? How do these tests help you with your diagnostic formulation and what do you think's next for this patient?

SUMU SIMON:            So, optical coherence tomography is a non-invasive imaging modality that is very widely used to evaluate diseases affecting the optic nerve, the macula and retina. It is quick and easy to perform, so, it can be done in a few minutes and does not use a dye. OCT is analogous to ultrasound imaging but it uses light instead of sound, so it is an optical imaging modality. It utilises a concept called inferometry to provide high resolution cross sectional tomographic images of the retina. It can provide cross sectional images of retina on a micron scale in situ and in real time. In other words, it can function as an optical biopsy of the retina and provide structural information about the layers of the retina.

It can also give information about thickness of the macula, thickness of the ganglion cell complex and retinal nerve fibre layer thickness. It gives useful information about optic disc morphology and peripapillary retinal nerve fibre thickening. This it useful for  monitoring glaucoma and other optic neuropathies. One thing to remember is that the media must be clear in order to perform an OCT- so it difficult to get a good OCT scan on a patient with an advanced cataract or an eye with dense vitreous haemorrhage.

Fundus fluorescein angiogram on the other hand is an invasive modality for imaging the disc, retina and the choroid.  The pupils need to be dilated. It also entails injecting fluorescein dye in the antecubital vein and thereafter serial fundus photographs are taken using a special fundus camera. It takes about 20 minutes to perform an FFA. Abnormalities manifest are detected on FFA as hyper or hypoflourescence.  It is particularly useful in evaluating vascular abnormalities affecting  the retina and macula. FFA is also useful  diagnosing choroidal ischemia.  So coming back to our patient, I'm presuming that the patient's left fundus examination is unremarkable and the vision is normal at this stage, Stephen?

STEPHEN BACCHI:       Yes

SUMU SIMON:            So, the OCT confirms a diagnosis of central retinal artery occlusion by demonstrating loss of normal retinal architecture in the right eye. In central retinal artery occlusion, OCT will also show hyper reflectivity of the inner layers of the retina due to retinal oedema. But there are similar retinal findings on OCT in the left eye and I am very concerned about an evolving central retinal artery occlusion in the left eye. When we look at the FFA findings, it shows decreased arterial filling not only in the right eye with central retinal artery occlusion, but there are similar findings in the left eye. So, delay in arterial filling is consistent with the diagnosis of central retinal artery occlusion but I'm concerned at the stage that this patient has an impending or evolving central retinal artery occlusion in the left eye. If the choroidal filling time is also delayed in this patient, that's useful information. Because what it tells us is that in addition to central retinal artery occlusion, this patient also highly likely has giant cell arteritis-related stenosis or occlusion of the ophthalmic artery or internal carotid artery on the ipsilateral side.

STEPHEN BACCHI:       Thank you. Giant cell arteritis was suspected, as has been discussed, and the diagnosis was later confirmed with a temporal artery biopsy though, that result was not available at this time. The patient was treated with one gram of IV methylprednisolone daily for three days. However, after two doses of the IV methylprednisolone there was a deterioration. So, the best corrected visual acuity declined to light perception in the right eye and counting fingers in the left eye. Examination showed a development of a new central retinal artery occlusion in the left eye despite appropriate medical therapy. Dr Simon, this is clearly a grave position with respect to this patient's vision. How commonly does this occur in GCA? And what are the risk factors for progressive course and what do you think will happen now for this patient?

SUMU SIMON:            So, this development is very unfortunate for the patient because it’s no longer a unilateral process, but it is a progressive and bilateral process. Progressive visual loss in giant cell arteritis can occur in up to  27.5 percent of eyes despite high dose IV methylprednisolone. We also know that progressive visual loss usually occurs within one week of commencing IVMP. The possible reasons for progressive visual loss despite high dose cortico-steroid in GCA patients could be that the dose is still not good enough. It could be that we have a highly aggressive disease in which the rate at which the inflammation is being controlled is not good enough. Or it could also be due to inflammation being resistant to the glucocorticoids. Or the other possibility to consider, is that this could be due to advanced luminal stenosis and thrombosis. In our patient, the vision loss is progressing despite IVMP, which was given promptly, and in this case glucocorticoid-resistant GCA needs to be considered, especially if the inflammatory markers are persistent and not showing a downward trend.

BRANDON STRETTON:           So, in view of contralateral spread of the inflammatory process, the treating team have prolonged the course of methylprednisolone to 5 days, now, and initiated a therapy known as salvage tocilizumab therapy. Subcutaneous tocilizumab was delivered following three doses of intravenous methylprednisolone and the patient’s best corrected visual acuity improved to hand movements in the right eye and 6/12 in the left eye within 48 hours of tocilizumab treatment. At 4-month follow-up, best corrected visual acuity had improved further to 6/9 in the left eye and remained stable at hand movements in the right eye. Additionally, his visual field index had improved by 9 percent. So Dr Simon, in view of this could you, maybe, please explain to us what tocilizumab is and how it works? And what’s potentially the rationale behind the treating team’s decision to introduce this therapy into this patient?

SUMU SIMON:            In recent years there has been significant developments in working out the immunopathogenesis of giant cell arteritis. We know that giant cell arteritis is characterized by chronic granulomatous inflammation and effects large and medium sized arteries. And the arteries have adventitia media and intima. In GCA following an unknown trigger there is breakdown of immune privilege in the adventitia where vascular dendritic cells recruit CD4 T-cells and this sets off a complex inflammatory cascade. The end result of vascular inflammation is luminal occlusion and ischaemia, as we all know. Interleukin-6 is significantly elevated in serum of untreated giant cell arteritis patients and some studies have shown that it is a more sensitive marker of disease activity than ESR.

Interleukin-6 is a proinflammatory multifunctional cytokine produced by a variety of cells, including T cells, B cells, monocytes and endothelial cells. Interleukin-6 induces T cell activation, B cell differentiation and also acute phase protein production. So, where does tocilizumab fit into the picture? Tocilizumab is a biologic disease-modifying drug. It is a recombinant humanized anti-interleukin-6 receptor antibody. Tocilizumab binds to the interleukin-6 receptor and prevents interleukin-6 from binding to its receptor Tocilizumab controls inflammation by inhibiting interleukin-6 signal transduction. Blocking interleukin-6 may halt the differentiation of CD4 cells into the T helper 17 cells and thereby reduce vascular inflammation. So, do you want me to discuss the considerations now?

BRANDON STRETTON:           I might just add, I think a few of our listeners would be familiar with tocilizumab, particularly in this setting of its use as a steroid-sparing agent. And also in other settings, such as treatment in the cytokine release syndrome that we see with a few haematological and cancer related treatments. I'd be interested, Dr Simon—so we know tocilizumab, chiefly its function has been, in part driven by the GiACTA trial, as a steroid-sparing agent—what was your rationale for starting it an acute salvage therapy. Was there any evidence that you had used previously to drive this decision? Or was it a spontaneous move? I’d be interested to hear.

SUMU SIMON:            So, we didn't have a robust data to back use of tocilizumab, in this setting. We came across three case reports that proved to be beneficial in either improving or stabilizing vision loss in patients with glucocorticoid-resistant, progressive giant cell arteritis-related visual loss. So that was a rationale for trialling tocilizumab in our patient.

STEPHEN BACCHI:       So thank you for that discussion, Brandon and Dr Simon, I think I've certainly learnt from it. You know, we as physicians need to be aware of the ophthalmic manifestations of systemic disorders. And as evidenced by this case, giant cell arteritis can be sight-threatening, bilaterally so, and prompt treatment and a structured approach to investigation is required. And sometimes very specialized treatments, including tocilizumab, are required. So just to wrap up the case for everyone, I'd be really interested in both of your perspectives on the key learning points from this case. So perhaps Brandon, you could give us some of your key thoughts. And then Dr Simon, if you could give us your final thoughts on the case be great. Thank you.

BRANDON STRETTON:           So I think one of the first learning points is the importance of early diagnosis and treatment in conditions like giant cell arteritis. This case really underscores the critical nature of timely diagnosis and aggressive treatment, in these conditions, the worst possible outcome being progression to legal blindness in this setting. The value of tocilizumab in refractory cases was certainly highlighted here. And I think that, in turn, speaks volumes to the fact that we're talking about an evidence hierarchy, where the gold standard is randomized control trials in many settings. However, I think, in this sort of setting that value is lended by case reports, and so the evidence hierarchy needs to start somewhere. And so, where possible publication of case reports should still be encouraged where they have the possibility to lend alternative treatment algorithms and considerations for patients in the future.

SUMU SIMON:            Thanks, Brandon. For me, the key points from this case was, one, detailed history-taking and clinical acumen are still key elements in establishing a timely diagnosis of giant cell arteritis. Second, amaurosis fugax warrants urgent investigations and warrants a referral to an ophthalmologist. Third, high index of suspicion for giant cell arteritis and prompt referral of giant cell arteritis suspects will ensure a best outcome for our patients. Fifth, progressive visual loss and elevated inflammatory markers should alert the clinician to glucocorticoid resistant giant cell arteritis. Next, multidisciplinary management is absolutely vital to reduce morbidity and mortality. And finally, targeted biologic agents may open up new treatment approaches for giant cell arteritis in the future, particularly in patients with progressive visual loss despite IVMP use. So those were the key learning points from this case for me.

STEPHEN BACCHI:       Thank you very much, Dr Simon. So that concludes our discussion of this case. So for more details, the full articles title is The Role of Tocilizumab in Glucocorticoid Resistant Giant Cell Arteritis: A Case Series and Literature Review. This was published in the Journal of Neuro-ophthalmology in 2023. The first author, Dr Brandon Stretton and senior author, Dr Sumu Simon, who have joined us today. We really appreciate your help learning from this patient's case. So thank you again.

MIC CAVAZZINI:          And thanks also to Dr Stephen Bacchi for driving this case report podcast. And as I said at the beginning, feel free to submit any ideas for cases to unpack or journal articles to dissect by writing to podcast@racp.edu.au. I’m thrilled to have more member-created content like this, and the previous Journal Club and IMJ On-Air episodes. It has always been a mission of Pomegranate Health to create a sense of collegiality among RACP members by letting you hear what other specialists are up to.

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