Lecture: Susac Syndrome: A Rare, but Important and Instructive Ophthalmologic Disease

Susac syndrome (SuS) is a rare immune-mediated occlusive microvascular endotheliopathy/basement membranopathy that causes ichemic injury to the retina, brain, and inner ear. SuS primarily affects young women 20-40 years of age . This disease is characterized by a clinical triad of encephalopathy, branch retinal artery occlusion (BRAO), and hearing loss, and is classically accompanied by “snowball” lesions in the corpus callosum on MRI. In this webinar presentation we will discuss the clinical features, immunopathogenesis, diagnosis, clinical course, and treatment of SuS—with an emphasis on ophthalmologic aspects, particularly the important role of serial Ultra Wide-Field Fluorescein Angiography (UWF-FA) in the management of patients with SuS.

Lecturer: Dr. Robert Rennebohm, Cleveland, Ohio, USA

Transcript

Dr. Rennebohm: Hello, everyone. I’m Dr. Rennebohm. Thank you for joining us for this talk on Susac Syndrome. Before I begin, let me explain that I’m not an ophthalmologist. I’m a Pediatric Rheumatologist who has focused on Susac Syndrome for the past 15 years or so. The ophthalmology that I do know, I learned primarily from John Susac and Dr. Martin Lubow, particularly from Marty. Marty was an ophthalmologist and a neuro-ophthalmologist at Ohio State University. For several years, John and Marty and I work closely together to better understand the Susac Syndrome. My role as a Rheumatologist was to compose and orchestrate the immunosuppressive treatment of Susac Syndrome.

Unfortunately, John died in 2012 and Marty died in 2015, so I would like to dedicate this lecture to John and Marty. Let me get my slides up. I realized that Susac Syndrome is quite rare. I imagine that many of you’ve never seen a case. But it’s an important and instructive disease, and as you’ll see it can be devastating for the patients and families. During the first half of this talk, I’m going to briefly discuss the clinical features, the immunopathogenesis, the diagnosis, the clinical course, and the treatment of Susac Syndrome. And then in the second half, I’ll focus more on the ophthalmologic aspects.

Susac Syndrome is an immune-mediated ischemia-producing occlusive microvascular endotheliopathy/basement membranopathy that primarily or that affects the brain and the inner ear and the retina, resulting in brain dysfunction chiefly, headache and cognitive dysfunction, a hearing loss, tinnitus, vestibular dysfunction, and retinal involvement was scotoma, visual field deficits due to BRAO.

This disease was first described by John Susac in 1979. John was a neurologist first and then a neuro-ophthalmologist. And it’s classic and complete forms Susac Syndrome is characterized by a clinical triad of encephalopathy, hearing loss and branch retinal artery occlusion. And by an MRI triad, the most important and characteristic feature being lesions in the central portion of the corpus callosum. Lesions in the deep gray matter and other white matter also often occur and leptomeningeal enhancements occur in approximately 33% of cases.

The characteristics MRI finding is one or more snowballs lesion in the central portion of the corpus callosum which are best seen on sagittal T2 FLAIR images. These snowballs lesions are due to ischemic injury that has caused edema, if not frank infarction of the callosal tissues in these locations. Susac Syndrome primarily affects young women between the ages of 20 and 40. Mean age of 32. The female to male ratio is 3.5 to 1. Affected men are also young between ages 20 and 40 usually. There have been several reports in children, mostly in adolescent but in on child as young as two. The elderly are not affected. Susac Syndrome does not occur in 70, 80, 90 years old. There have been approximately 450 reported cases in the world’s literature.

The ethnic distribution is unclear. Most of the reported patients have been Caucasian. Susac Syndrome is often misdiagnosed usually as atypical MS, but sometimes as atypical ADEM, or atypical primary angiitis of the central nervous system. I imagine that many cases go undiagnosed and untreated, particularly patients with partial versions or atypical features. Some further words about the ethnicity of patients, most patients have been Caucasian, primarily from Europe, the United States, and Canada, particularly from the Netherlands, Belgium, Germany, and the United States, not so much form Russia, for some reason. There have been only rare reports from Asia, three reported cases from India and three reported cases from China, despite their combined population of 2.7 billion people. It may be more common in Jewish populations I say that because I’ve been aware of approximately 25 cases in Israel, which has a population of only 9 million. It is not uncommon in South American countries. It has been rare in African-Americans and there have been no reports from Africa of black patients with Susac Syndrome.

Some comments about the immunopathogenesis. Our current concept is that the microvascular endothelial cells are the primary site of immune misbehaviour and injury. This is a drawing of a normal arterial with a normal thin basement membrane and normal endothelial cells and a wide open lumen. In Susac Syndrome the endothelial cells appeared to become abnormally activated and immunologically injured and swollen. So I said the capillary or small arterial becomes a least partially occluded resulting in decreased blood flow through the vessel. In severe cases the endothelial cells become so swollen that the vessel becomes nearly or completely swollen shut resulting in little or no blood flow through the vessel. In the brain it is the microvasculature of the corpus callosum that is predominantly and most obviously affected in Susac Syndrome, but capillary and arterials throughout the brain including in the cortex can also be affected.

This is a drawing of a normal microvascular network perfusing the genu of the corpus callosum with its normal endothelial cells and wide open lumens providing normal blood flow. Here vessels that have become partially swollen leading to is chemic injury to that part of the callosum they perfuse. This ischemic injury leads to at least temporary dysfunction, the injury and dysfunction are potentially reversible if the endothelial swelling is reversed before permanent harm occurs. And here’s an example of vessels that have become completely swollen shut due to severe and endothelial cells swelling such that no blood flow is delivered to the part of the callosum they perfuse. That part of the callosum is at risk of sustaining irreversible permanent ischemic damage unless the swelling is quickly reversed. In this drawing the four microvascular networks and the posterior half of the callosum are severely affected causing intense ischemic injury to the parts of the callosum they perfused. In contrast three of the six networks in the anterior half of the callosum are unaffected and the other three are only mild to moderately affected.

It is this ischemic injury that causes the snowball lesions on MRI has shown in this slide where we see large snowball lesions in the posterior half of the callosum unless severe lesions anteriorly. In the Susac Syndrome the same inclusive microvascular endotheliopathy occurs in the retina, this well seen angiogram demonstrates several typical branch retinal artery occlusions BRAO’s at points A and B for example. Just as occlusion of the microvasculature and the corpus callosum causes white ischemic snowball lesions on MRI, occlusion of the microvasculature and the retina causes ischemic cotton wool spots. These next several slides demonstrate the value of fluorescein angiography in helping us to diagnose as well as follow and understand what is occurring in Susac Syndrome. This is a normal retinal arterial, note the thin healthy basement membrane of the vessel, the normal healthy endothelial cells that line the inner aspect of the vessel wall, the tight junctions that normally hold the endothelial cells tightly together and the normal free flow of die through the vessel.

One of the important tasks of healthy endothelial cells is to maintain the integrity of the basement membrane. The health of the basement membrane depends greatly on the health of the endothelial cells. Here is a retinal arterial in a patient with Susac Syndrome. The endothelial cells on the left are moderately swollen leading to partial occlusion of the vessel and therefore diminished die flow and of course diminished blood flow. The endothelial cells on the right are severely swollen leading to complete occlusion and complete obstruction of die float. Note too that the endothelial cells have separated from each other allowing die to seep into places where the dye doesn’t belong. This slide depicts the phenomenon of hyper fluorescence in leakage associated with sick and endothelial cells and a sick basement membrane.

The endothelial cells are moderately swollen leading to partial occlusion of the vessel and injury to the endothelial cells causes them to partially detach from the basement membrane as well as from each other and this allows die to not only seep in between the endothelial cells, but also to increasingly accumulate and stagnate in the space between the endothelial cells and the basement membrane. A phenomenon that results in persistent vessel wall hyper fluorescence. Furthermore note that some of the die is oozing through or leaking through the sick basement membrane, this leakage is occurring because the sick and endothelial cells have not been able to maintain the health of the basement membrane. The basement membrane becomes abnormally porous allowing die to leak through it, hence the leakage.

This slide demonstrates to areas of obvious hyper fluorescence and leakage and a patient with Susac Syndrome with only partial occlusion. Note that the hyper fluorescence in leakage occurs in relatively short segments of these vessels and that’s why it’s best called segmental hyper fluorescence and leakage in the lower right is the third area of more subtle leakage without much hyper fluorescence. Here’s another example of segmental hyper fluorescence and leakage, this slide shows three areas of segmental leakage with only minimal hyper fluorescence. And this slide demonstrates all three phenomena an obvious BRAO and two areas of intense segmental hyper fluorescence with narrowing between those two segments. This is a histopathology study of the retina from an autopsied case of Susac Syndrome published by McLeod several years ago. It demonstrates the most extreme example of Susa microvascular endotheliopathy namely capillary dropout, note the large black zone in which there are no capillaries.

This zone is surrounded by mostly normal capillary networks, but there are no capillaries within this black zone of capillary drop out. All of the capillaries that used to be in this location have perished disintegrated and disappeared. The endotheliopathy in this zone was so severe that the endothelial cells died or apoptosed and disintegrated and because there were no longer any endothelial cells to maintain the health of the basement memory and the basement membrane became so sick that it also disintegrated with no endothelial cells and no basement membrane, there could be no capillary. So this is capillary drop out.

The next several slides demonstrate the chronic residual basement membrane abnormalities that can occur in Susac Syndrome when the endothelial cells are chronically so sick that they can’t maintain the basement membrane. This would be a normal thin basement membrane. Here’s an arterial with moderate endothelial cell sickness and swelling that has led to moderate thickening and disorganization of the basement membrane. And here is a more severe case with a greater degree of basement membrane thickening, duplication, and disorganization. The basement membrane becomes sloppily maintained an abnormally porous. I hasten to add that these basement membrane abnormalities are reflections of chronic inadequately controlled endotheliopathy. This basement membranopathy can be completely prevented or at least minimized by adequately controlling the endotheliopathy. But once these basement membrane abnormalities have occurred they are irreversible.

We recently published an electron microscopy study of the brain microvascular five patients with Susac Syndrome. This is an EM image of a normal brain capillary and note the normal thin delicate basement membrane also called the basement laminar, which has an inner and an outer layer and is normal normally quite thin and also noticed the delicate endothelial cells in the wide open lumen. Here’s an EM image of an abnormal capillary in Susac Syndrome, note the grossly thickened basement membrane, the enlarged sick endothelial cell and the relatively narrowed lumen which happens to have two red blood cells in it. Here’s another example of a capillary and Susac Syndrome. The basement membrane is grossly mal-maintained mal-constructed and thickened and there’s abnormal chaotic deposition of collagen and amorphous material within the basement membrane. And the endothelial cell is sick and the lumen is narrowed.

So Susac Syndrome is both an endotheliopathy and a basement membranopathy. And as you can imagine this best, this basement membranopathy has the potential to cause abnormal diffusion of oxygen. This same inclusive microvascular endotheliopathy also occurs in the inner ear, this slide depicts the microvasculature of the cochlea and the vestibular apparatus. In Susac Syndrome the tip of the delicate cochlea is particularly vulnerable and likely to suffer from ill perfusion with occlusion due to the inclusive microvascular endotheliopathy since the tip of the cochlea is responsible for low frequency hearing, ill profusion of it leads to low frequency sensorineural hearing loss. And then occlusion of the microvascular to the vestibular apparatus results in vertigo. Here is an audiogram showing the low frequency sensorineural hearing loss that is typical of Susac Syndrome. So in Susac Syndrome the endothelial cells of the microvasculature and the brain retina and inner ear somehow become immunologically injured and swell. This endothelial swelling narrows the lumena of these vessels. The tissue is perfused by these vessels suffer varying degrees of ischemic injury ranging from temporary reversible dysfunction to potential irreversible ischemic damage.

The brain, retina, and cochlea either suffer varying degrees of temporary dysfunction or permanent damage. And in addition the sick endothelial cells beget sick basement membranes and you get ugly basement memory and thickening which could lead to oxygen diffusion deficits. So Susac Syndrome is an immune-mediated ischemia producing inclusive microvascular endotheliopathy and basement membranopathy that results in the typical Susak Clinical triad of encephalopathy with associated corpus callosal lesions on MRI and with retinal disease characterized by scotoma, visual field deficits due to well as segmental hyper fluorescence and leakage and inner ear dysfunction characterized by hearing loss, tinnitus, and vertigo. Some further comments about the brain manifestations of Susac Syndrome the most common are headache and cognitive dysfunction. The headaches are often migraine like, the cognitive dysfunction is typically short term memory loss, executive dysfunction, confusion and disorientation, personality change, and emotional liability are common. Psychiatric symptoms including paranoia are common. Paresthesias are very common. Hemiparesis are little less common. Ataxia and apraxia are common and neurogenic bladder which is central in origin is common. Seizures are actually very rare.

Among the worst possible outcomes of Susac Syndrome are dementia and severe spasticity. Some patients end up with severe lifelong mental and physical disability. Profound deafness can require cochlear implants and partial blindness can occur due to the cumulative visual loss from BRAO’s. I’ve been aware of at least six patients who have died from Susac Syndrome all because of overwhelming severe diffuse microvascular disease in their brain. So this is certainly can be a very serious disease especially in its most severe form. How do we diagnose Susac Syndrome, the first step is to look for evidence of the typical Susac Syndrome clinical triad. However, it must be realized that when patients with Susac Syndrome my first brought to medical attention all three components of the triad are present in less than 20% of the cases. Usually only one or two of the components of the triad are present with the other components developing days or weeks or months later.

Any one of the components of the clinical triad can be the first and only manifestation at the time of presentation. For example, some patients present only with the encephalopathy followed weeks later by BRAO and even after that the hearing loss. Other patients present with isolated BRAO and no encephalopathy or hearing loss at that time but with the encephalopathy and hearing loss developing later. And other patients present with isolated hearing loss with the other two components appearing later. Notice also that in a given patient the severity of each component is not necessarily equal. The important message here for ophthalmologists is that if you see a patient with isolated BRAO’s especially if they are under age 45 you should think of Susac Syndrome because encephalopathy or hearing loss which may not be present at that time may eventually follow and permit and eventual diagnosis of Susac Syndrome. Speaking of isolated BRAO you may recall that in 1994 Don Gass described a small series of patients who experience recurrent episodes of isolated unexplained BRAO. He called this phenomenon idiopathic recurrent BRAO, but is it possible that this entity represents Susac retinal vasculopathy without Susac CNS vasculopathy and without Susac inner ear vasculopathy. And if so should such patients be treated at least briefly with a course of immunosuppression.

After looking for the clinical try the next step is to obtain an MRI scan to determine whether the patient has MRI abnormalities typical of Susac Syndrome, this is another example of corpus callosal lesions of different sizes shapes and severity. Note that some of these snowball lesions are not round they’re actually rectangular. Another MRI abnormality to look for his corpus callosal holes which are caused by the ischemic damage to the callosum in those locations and these are best seen on sagittal t1 images. Analysis of CSF often provides support for a diagnosis of Susac Syndrome, CSF protein, elevation occurs in 80%. CSF pleocytos is in about 50%.Usual blood testing is not very helpful in the evaluation of Susac Syndrome, there’s usually no evidence of systemic inflammation because this is not a systemic inflammatory disease process. Accordingly the said rate, the CRP and the CBC are expected to be normal. Anti-endothelial cell antibodies have frequently been demonstrated in patients with Susac Syndrome, but this probably represents a non-specific epiphenomena and is not particularly helpful.

What about the clinical course of Susac Syndrome. Some patients follow a monocyclic course particularly regarding their brain involvement and by this I mean the immune system makes the Susac mistake only once and eventually corrects that mistake never to make it again. The intensity of the mistake making in the brain for example may be mild, moderate, or severe, and the duration of the mistake making in the brain again maybe relatively short for 6 to 12 months or longer 12 to 18 months or it may take two years before the monocyclic course runs its course. By definition a course is termed monocyclic if it ends within two years and the disease activity never returns. Other patients experience of polycyclic course meaning that their immune system makes the mistake and then fully corrects the mistake but then repeatedly makes the same mistake over and over again. This is best exemplified by Susac patients who experience recurrent episodes of BRAO. Other patients experience a chronic continuous course primarily involving the brain meaning that their immune system continually makes the Susac mistake’s at a mild, moderate, or severe or fluctuating level of intensity for more than two years often for 3 to 6 years sometimes much longer even up to 10 years or longer.

I should add that in an individual patient, the brain involvement may follow monocyclic course while the retinal involvement follows a polycyclic course. How do we treat Susac Syndrome? Current treatment is based on the treatment that has worked well for severe juvenile dermatomyositis. JDM has seemed to be the best model for Susac Syndrome, so we’ve tried to borrow as much of what we’ve learned with JDM and applied it to Susac Syndrome. And that treatment consists of IV pulse methylprednisolone initially followed by tapering dose of prednisone and they’re also treat with IVIG and mycophenolate mofetil or cyclophosphamide and in some cases Rituximab is added. This is the typical first 12 months of treatment for a patient with typical moderate-to-severe Susac Syndrome. It starts with 3 to 5 consecutive daily pulses of methylprednisolone and then high dose oral prednisone with subsequent slow tapering and early introduction of IVIG and MMF. The monthly IVIG and the MMF protect the patient while the prednisone is slowly and necessarily tapered. A faster tapering of prednisone can occurrence in some patients.

For particularly severe disease an option is to use IV pulse cyclophosphamide rather than MMF with plans to switch to MMF after 6 to 7 monthly pulses of cyclophosphamide or sometimes after 3 to 4 months of cyclophosphamide. Another option for severe disease is to add Rituximab usually in combination with MMF, but sometimes even in combination with Cytoxan or cyclophosphamide. The goal of treatment is to help a microvasculature that is nearly swollen shut to become only personally swollen shut and then returned to normal. Now let’s focus more on the ophthalmological aspects of Susac Syndrome particularly the importance of carefully following patients with serial FA studies. These next several slides share instructive details about the five year clinical course of Susac retinal vasculopathy experienced by a 34-year-old female who presented with acute scotoma and also initially had brain and inner ear involvement. This is her initial FA study showing multiple severe threatening BRAO’s particularly in the inferior temporal region and superior region of the left eye.

She had less a less severe BRAO in the right eye, this is a superior view of the BRAO in the left eye, I note that she also had a nasal BRAO. In the left eye there was also a different vessel with segmental hyper fluorescence and leakage with no occlusion. This combination of BRAO in one or more vessels and segmental hyper fluorescence and leakage in other vessels is very typical of Susac Syndrome and would not occur if a BRAO were due to embolism or thrombosis. On this same initial FA study, she also had a BRAO in the temporal periphery of the right eye. And here is her left eye at the seven minute 56 second mark still showing poor perfusion. She was probably treated with three consecutive daily 1 g pulses of IV methylprednisolone, 2 g per kilogram of IVIG followed by every two week IVIG. She was also placed on high dose oral prednisone with slow tapering and was also quickly started on mycophenolate mofetil and Rituximab. And 3.5 months later you can see that a repeat FA study revealed marked improvement in blood flow.

Her initial brain involvement responded well to initial treatment and has been minimally problematic for the past five years. So she followed a monocyclic course as far as your brain involvement was concerned. Her inner ear disease responded slowly initially, but she has had only occasional mild to moderate inner ear symptoms since then. Her main problem has been her recurrent episodes of Susac retinal vasculopathy throughout this past five years as documented by serial FA studies which I’ll share with you in a moment. And this has occurred despite use of the following medications throughout the past five years corticosteroid, IVIG, MMF, Rituximab with eventual substitution of tacrolimus for the MMF. So the main driver of her treatment decisions has been the recurrent episodes of active retinal disease and her ophthalmologist has been the most important member of her Susak team. She has undergone a total of 30 FA studies during the five-year course of her Susac Syndrome. I hasten to add that she has tolerate all of these FA studies very well, I realize that’s a lot of FA studies, but the reason for so many FA studies is that only four of the 30 studies did not show — only four of the 30 studies have not shown disease activity, 26 of the 30 studies have shown newly involved vessels with new active segmental hyper fluorescence and leakage. And seven of the 30 studies have revealed new BRAO’s.

When immunosuppression was tapered too much and too soon flareups tended to occur, these findings forced us to do the frequent follow up FA studies and frequent adjustment of immunosuppression. The good news is that every time segmental hyper fluorescence was noted it resolved by the time of the next study without evident residual damage. And that that resolution occurred either spontaneously or due to a least temporary escalation of immunosuppression. Often however the previous segmental hyper fluorescence and leakage was replaced in the next study by new segmental hyper fluorescence and leakage and in a previously normal vessel. For example two years into the course of her disease a routine follow up FA on May 29,2017, revealed new active hyper fluorescence and leakage in the right eye, but seven weeks later in July that I profess it’s a leakage had resolved despite slight interval tapering of her immunosuppression. Then two months later in September of 17 new segmental hyper fluorescence and leakage developed in vessels that had been normal back in July this flare up had occurred after minimal interval tapering of immunosuppression, but then two months later these vessels looked normal after brief escalation of treatment.

On another occasion in October of 2019, she developed new hyper fluorescence and leakage in two vessels in the far periphery, but three months later in January those two vessels looked normal but a new area of segmental hyper fluorescence and leakage had developed in a different fortunately very tiny vessel. Although she has continued to experience recurrent episodes of active Susac retinal vasculopathy throughout the past, throughout the five years of her Susac Syndrome, all of her episodes of hyper fluorescence and leakage have resolved uneventfully from one FA study to the next often spontaneously. We’ve been able to gradually taper her immunosuppression throughout these five years. During the first year she was unable to tolerate less than 40 mg of prednisone per day while also receiving every two week pulses of IVMP and every two week IVIG as well as MMF and every six months for Rituximab. Now she is on 5 mg per day of prednisone, 3 mg per day of Tacrolimus and every three week IVIG and she’s no longer on Rituximab. Her cereal FA findings have provided invaluable guidance, they helped us to recognize when it was safe to further taper immunosuppression and when it was necessary to briefly escalator immunosuppression. Our goal all along was to provide enough immunosuppression to prevent new episodes of segmental hyper fluorescence and leakage from evolving into BRAO while at the same time trying to minimize side effects from the immunosuppression.

In this way we were able to largely protect her eyes during the first month of her Susac Syndrome she was aware of a 75% loss of visual field on the left and a 15% loss on the right at the five year mark, this was the same or only minimally worse. Her cereal FA studies have continually showed damaged capillaries in the retinal periphery of both eyes, but these changes developed very early in the course of her Susac Syndrome and of appeared to remain stable ever since. For example, all of her serial FA studies over this past five years have shown the same capillary damage unchanging in the superior far retinal periphery of the left eye. On this study she also happened to have a new area of active hyper fluorescence and leakage, So this FA shows both old inactive disease and a small area of new active disease. This FA study shows a large area of capillary non-perfusion probably due to capillary disintegration and disappearance, capillary dropout. Another sign of capillary damage is the microaneurysm formation. Here’s another area of capillary damage in the far periphery of her left eye and these areas all look the same on every FA study that she had over these five years.

This is the previously shown area of capillary damage, it is more hyperfluorescent on the eight minute image because the damage capillaries are abnormally dilated and have abnormally accumulated die. So this increased hyper increased fluorescence at the end of the study is not because of ongoing active disease. On at the 10 minute mark you could see increased hyper fluorescence in these damaged capillaries. It is sometimes difficult though to know whether such images like this are simply showing damage from past active but no longer active disease or if there is some active disease still occurring in addition to the damage. Careful serial comparisons are necessary to sort this out, if this appearance never changes on cereal FA studies it probably represents only damage without any ongoing active disease. So points of emphasis things we learned from this patient in particular, many patients with Susac Syndrome experience recurrent episodes of active retinal vasculopathy for several years despite having no difficulty or far less difficulty with Susac involvement of their brain and inner ear during those years.

Sometimes this retinal problem can be very difficult to treat especially during the first 1 to 2 years, recurrences may continue to occur for several years, but eventually stop occurring. Episodes may involve the large proximal branches, arterials of the retinal artery or small distal branches in the far periphery or moderate sized branches in the mid periphery and small branches in the mid periphery and near the optic disc or immaculate can also be involved. In a given vessel the disease is typically segmental and falls along a spectrum from complete occlusion to partial occlusion to segmental hyper fluorescence and leakage with little or no occlusion. Episodes of segmental hyper fluorescence and leakage with little or no occlusion are typically asymptomatic and BRAO can also be asymptomatic if in the far periphery or in a tiny branch of more proximal vessel. In Susac Syndrome much of the action sometimes all of the action is in the far periphery, sometimes only in the far periphery and this action is sometimes detectable only with use of ultrawide field FA equipment. So serial ultra-wide field FA studies are essential for optimal diagnosis and management of Susac Syndrome. Conventional FA does not adequately visualize the far periphery.

Many patients require every 2 to 4 months serial FA studies during at least parts of their clinical course if they’re having lots of difficulty with the retinal component. Each new FA study needs to be carefully compared to previous ones in order to optimally interpret abnormalities. As you can imagine this is a painstaking and time consuming process, but it needs to be done. Patients who are receiving considerable immunosuppression may despite this experience recurrent episodes of asymptomatic segmental hyper fluorescence and leakage which however might have become episodes of harmful BRAO if the patient had not been on that amount of immunosuppression. Episodes of segmental hyper fluorescence and leakage have the potential to evolve into regrettable BRAO there by raising consideration of escalation of immunosuppression but may also have the potential to resolve spontaneously and harmlessly even when immunosuppression is kept the same. It’s hard to know with certainty however whether a given episode of segmental hyper fluorescence and leakage is destined to resolve spontaneously or is destined to evolve into a threatening BRAO.

Episodes of segmental hyper fluorescence and leakage in large proximal vessels and/or vessels near the macular are worrisome and warrant at least brief escalation of immunosuppression, sometimes urgent escalation. For segmental hyper fluorescence and leakage and tiny capillaries in the far periphery, careful observation and follow up without changing immunosuppression is often appropriate. During the early weeks and months of unrecognized or inadequately controlled Susac Syndrome many patients experience severe irreversible damage to the capillary networks in the far periphery particularly if they’re Susac Syndrome goes unrecognized or is initially severe and/or inadequately controlled. The frequency and severity of recurrences gradually decreases, decrease over a period of several years, eventually recurrences stop altogether, but sometimes that can take 10 years or longer to occur.

In the meantime careful monitoring with FA and careful adjustments in medication are essential. The benefits of immunosuppression always need to be balanced against the risks of the medications and the risks of inadequately suppressed disease. Patients deserve to have a voice in discussions and decisions about treatment. Some comments about OCT. OCT can be helpful in diagnosis. Susac Syndrome causes a ischemic injury to the inner layers of the retina particularly the retinal nerve fiber layer as evidenced by the mark thinning of the inner layer at the two large arrows on this slide. The outer layers of the retina are typically spared, remember that the inner layers are supplied by the retinal vasculature whereas the outer layer is supplied by the choroid vasculature. Here is a serial OCT images before and after an acute BRAO episode up at the top you can see in the normal thickness of the retinal nerve fiber layer. Then during the acute episode there’s actually swelling of the retinal nerve fiber layer, so it looks thicker, but then at the 14-day market begins to thin and increasingly thins over time and is very thin at the one year mark.

Here’s another example of atrophy of the inter retinal layers due to ischemic injury from BRAO on OCT. OCT angiography has been of some interest, I’m not sure it’s been very helpful frankly from a clinical standpoint. This profusion map shows temporal parafoveal hypoperfusion in the superficial in deep capillary plexuses the red asterisks. But then six months later there’s improved perfusion of previously hyperperfused areas, note the yellow arrows. Here’s a little bit better example of multiple areas of hypoperfusion on the top left and then six months later better profusion in this location. Initially it was thought that the choroid is spared in Susac Syndrome, this notion was based on an ICGA study by Martinet that was a study of seven patients with Susac Syndrome, all had FA evidence of BRAO and segmental hyper fluorescence and leakage and none had abnormalities on ICGA. Subsequently, there was a study of a single patient published by Alaska’s that provided evidence that the choroidal vasculature can sometimes be affected, note the zone of choroidal capillary non profusion in the middle frame and the staining of choroidal vascular segments in the third frame.

I would add that in our recently published autopsy study of the eye, we documented choroidal involvement. In that study, we documented presence of perivascular infiltration of choroidal vessels. So I think we can conclude that the choroid is not always spared. Just for completeness I should add that central retinal artery occlusion has rarely been reported in Susac Syndrome, but it can occur and also for completeness I should mention the gass plaques that can be sometimes seen upon simple fundoscopy. These gass plaques are due to chronic accumulation of serious deposits along the inner walls of the arterial and here’s an example of extensive capillary damage and as such instances pan retinal photocoagulation maybe necessary or warranted. So that’s the end of this talk on Susac Syndrome. Again it’s a rare disease, but I think it’s a very important and instructive disease and most importantly is potentially devastating for patients and the families who have to deal with it. I would like to close with a tribute to John Susac, this is a[indiscernible] [00:48:10] painting of Don Quixote.

John was a really Quixote who undauntedly led the charge in understanding and treating Susac Syndrome, while historically the rest of the medical profession particularly the health insurance companies have been pretty much like Sancho a little slow to develop awareness and concern about this disease. So inspired by Dr. Susac we should do all we can to help patients with Susac Syndrome. So thank you very much and I just want to extend a special thanks to the late John Susac and the late Martin Lubow. Thank you.

The first question is what are the common features of Susac Syndrome and multiple sclerosis. Is there any common etiopathology for these diseases? These diseases have completely different ideologies as I’ve shown Susac Syndrome is a microvascular endotheliopathy and microvascular disease whereas multiple sclerosis is really does not involve the microvasculature and is more of a demyelinating disease. We think that Susac Syndrome is probably mediated by cytotoxic t-cells or possibly by type 1 interferon dysregulation. So the pathogenesis is different and the MRI features although they can look similar are quite different. The main thing to realize is that with Susac Syndrome, the corpus callosal lesions are in the central portion of the corpus callosum whereas in multiple sclerosis the lesions are more pericallosal are on the edges of the callosum and not in the central portion of the corpus callosum.

Next question is eyes there any age group in which this is very prevalent. Well yes it is, most prevalent in people between ages 20 and 40. It is sometimes seen in adolescence is usually not seen in children under at the adolescent age range and it’s not seen in the elderly. How under diagnosed is this condition is the next question. I think it’s often under diagnosed. When all three components of the clinical triad are present and when the typical corpus callosal lesions are evident then it’s an easy diagnosis to make and people are very comfortable making the diagnosis. If there’s only one or two components or if the callosal involvement is unimpressive or even not present, but there’s extra callosal white matter disease, then even if all three components were present doctors are hesitant to make a diagnosis understandably because the callosal lesions are not present. Plus I think there are lots of physicians who have never heard of Susac Syndrome. Very often it’s the neuroradiologist who looks at the MRI and puts in his report, please consider Susac Syndrome because of the corpus callosal lesions.

Next question is may I ask what initiates the pathogenesis of the syndrome and are there any aggravating factors. We still have to speculate as to what causes Susac Syndrome. My own personal feeling is that there is probably or possibly a dysregulation of type I interferon within the endothelial cells in the microvasculature of these three particular organs. And what happens is the type 1 interferon system gets up regulated often spontaneously and then this leads to a lot of downstream immune [indiscernible] [00:53:08] including activation of CD8-positive cytotoxic T-cells which then can injure the endothelial cells and cause the swelling. In some instances it’s possible that a viral infection triggers off this excessive immune and inappropriate immune reaction, but viral studies have not shown consistently that any particular viruses are responsible. I think it’s possible that emotional stress can predispose to this type of immune dysregulation occurring, but again that’s pure speculation. A lot of patients have noticed that their Susac Syndrome developed during times of major stress, but times of major stress are very common, so that’s hard to sort out.

I do think there is probably going to turn out to be an immunogenetic predisposition to the development of Susac Syndrome. I’ve been very interested to see that it’s that it seems to be more common in Israel, for example, and it is very uncommon in other countries. So I think there’s going to be some very fruitful research in the future looking at the immunogenetics of Susac Syndrome. Next question is why is immunologic injury limited to the brain, cochlear, and retina. Again all we can do is speculate, but if you think about it, the brain, the cochlear and the retina are three of the most delicate organs in the human body and it may well be that the endothelial cells in the microvasculature in these organs are programmed to immunologically fight off potentially threatening viral infection that it detects, because part of our immune system resides in the endothelial cells. And that’s what I was mentioning earlier it could be that in some patients the type one interferon in the endothelial cells in these particular organs flies into action too quickly and too violently and it results in the endothelial cells actually getting injured while they’re trying to protect our precious organs from viral invasion, and so that’s one possibility.

It’s also possible that there are different antigens on the endothelial cells in these tissues compared to antigens on the endothelial cells in the microvasculature of other organs. I should add that even though the main organs that are affected in Susac Syndrome are the brain, the retina, and the cochlea. There are other organs that can be affected. George Petty an neurologist at the Mayo Clinic many years ago did muscle biopsies on patients with Susac who had no muscle symptoms. And I think it was three of the five muscle biopsies showed evidence of microvascular disease a typical of what we’ve subsequently shown in the brain in Susac Syndrome. Also some patients develop a livedoid type of rash, so the microvasculature of the skin is also probably affected. And it’s possible that the GI tract is involved in some patients as well.

Let me go on to another question. Okay is there any other modality of investigation to follow up these patients in case they have flourishing die allergy. I haven’t encountered that problem nor have I’ve been aware of other doctors who have been taking care of Susac patients encountering that problem and not being an ophthalmologist, I’m not sure what the alternatives would be. The OCT unfortunately doesn’t pick up evidence of active disease necessarily, it just picks up evidence of damage from past active disease unless you happen to catch it during the acute phase of the injuring event. So OCT is one option. I’m not sure if the OCT Angio would be helpful, but that would be one other modality to consider. Let me go on to the next question. Considering the rarity of Susac Syndrome and it’s lack of systemic markers and other ideologies of BRAO in young patients, what blood tests or other imaging tests should be ordered to gather the most information regarding the cause of BRAO in this group of young patients.

Well the first step would be to get an MRI scan even if the patient is not having any brain symptoms because the MRI scan might show corpus callosal lesions even though the patient is a symptomatic from a brain standpoint. Similarly is worth getting an audiogram because the patient may not be aware of subtle low frequency hearing loss. So getting an audiogram is helpful. Right now we don’t have any good laboratory markers to help us in the diagnosis or follow up of patients. Let’s see. Next question is as this convey a devastating visual condition is referring to a low vision specialist a part of the management for the patient to cope and somehow continue basic activities of daily living at least. Well fortunately it’s rare to have devastating visual damage. I’ve been aware of one patient who lost 90% of his visual field in one eye due to recurrent episodes of BRAO over several years that cumulatively knocked out one area after another. I would hasten to add that that patient was slow to receive adequate immunosuppressive treatment and I would like to think that if Susac Syndrome is diagnosed promptly and early and if it’s treated adequately aggressively, it would be possible to prevent this from becoming such devastating to them.

And I think in the case I presented of the 34 year old female most of the damaged that resulted in her 75% visual loss in her left eye that occurred even before she was diagnosed probably or at least within the first few weeks or month or two of her disease. So the key to preventing the devastating visual loss is early prompt aggressive treatment and close follow up. Well thank you very much all of you who attended this talk. Thank you.

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June 24, 2020

Last Updated: September 12, 2022

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