Diagnostic Criteria and Treatment Algorithm for Susac Syndrome

Background: Susac syndrome (SS) classically presents with the clinical triad of retinal artery occlusion, sensorineural hearing loss, and encephalopathy and the neuroimaging triad of white matter lesions, deep gray matter lesions, and leptomeningeal disease. However, patients can present with an incomplete clinical or neuroimaging triads making diagnosis difficult in certain situations. A standard treatment paradigm also is lacking in this illness. It is important for neuro-ophthalmologists to recognize clinical and radiographic findings that are pathognomonic for this syndrome and have a basic understanding of the available treatment options. Evidence acquisition: Review of medical literature. Results: A definite diagnosis of SS is made when the clinical triad or the neuroimaging triad is present. There are numerous reports of 2 other imaging findings in this condition: arteriolar wall hyperfluorescence (AWH) on fluorescein angiography in retinal arterioles remote from retinal ischemia and central callosal lesions on MRI. Both of these imaging findings are diagnostic of SS. Gass plaques in retinal arterioles are almost always seen in the acute phase of the illness but are not pathognomonic for SS. The most common medications used in this syndrome are corticosteroids and intravenous immunoglobulin. A number of other medications have been used including mycopheolate, rituximab, azathioprine, and cyclophosphamide. Conclusions: In the absence of the clinical triad or magnetic resonance imaging triad for SS, AWH remote from retinal vascular injury and central callosal lesions are confirmatory of the diagnosis because they have never been described in any other condition. The presence of Gass plaques in retinal arterioles should strongly suggest the diagnosis. Despite the lack of clinical trial data, patients with SS must be treated promptly and aggressively. In more fulminant cases, addition of mycophenolate mofetil or rituximab is required, followed by cyclophosphamide when disease is refractory to other medications.

State-of-the-Art Review Section Editors: Fiona Costello, MD, FRCP(C) Sashank Prasad, MD Diagnostic Criteria and Treatment Algorithm for Susac Syndrome Robert A. Egan, MD Background: Susac syndrome (SS) classically presents with the clinical triad of retinal artery occlusion, sensorineural hearing loss, and encephalopathy and the neuroimaging triad of white matter lesions, deep gray matter lesions, and leptomeningeal disease. However, patients can present with an incomplete clinical or neuroimaging triads making diagnosis difficult in certain situations. A standard treatment paradigm also is lacking in this illness. It is important for neuro-ophthalmologists to recognize clinical and radiographic findings that are pathognomonic for this syndrome and have a basic understanding of the available treatment options. Evidence Acquisition: Review of medical literature. Results: A definite diagnosis of SS is made when the clinical triad or the neuroimaging triad is present. There are numerous reports of 2 other imaging findings in this condition: arteriolar wall hyperfluorescence (AWH) on fluorescein angiography in retinal arterioles remote from retinal ischemia and central callosal lesions on MRI. Both of these imaging findings are diagnostic of SS. Gass plaques in retinal arterioles are almost always seen in the acute phase of the illness but are not pathognomonic for SS. The most common medications used in this syndrome are corticosteroids and intravenous immunoglobulin. A number of other medications have been used including mycopheolate, rituximab, azathioprine, and cyclophosphamide. Conclusions: In the absence of the clinical triad or magnetic resonance imaging triad for SS, AWH remote from retinal vascular injury and central callosal lesions are confirmatory of the diagnosis because they have never been described in any other condition. The presence of Gass plaques in retinal arterioles should strongly suggest the diagnosis. Despite the lack of clinical trial data, patients with SS must be treated promptly and aggressively. In more fulminant cases, addition of mycophenolate mofetil or rituximab is required, followed by cyclophosphamide when disease is refractory to other medications. Journal of Neuro-Ophthalmology 2019;39:60-67 doi: 10.1097/WNO.0000000000000677 © 2018 by North American Neuro-Ophthalmology Society Department of Neurology and Ophthalmology, Rockwood Clinic Neuro-Ophthalmology, Spokane, Washington. The author reports no conflicts of interest. Address correspondence to Robert A. Egan, Department of Neurology and Ophthalmology, Rockwood Clinic, 910 W. 5th Avenue, Suite 1000, Spokane, WA 99204; E-mail: [e-mail] 60 S usac syndrome (SS) classically presents with the clinical triad of vision loss, hearing loss, and encephalopathy (1,2), which is caused by vasculo-occlusive disease affecting the retina, inner ear, and brain. Four of 5 patients are female, and mean age of disease onset is 32 years (3). The diagnosis is easily made when the clinical triad is present but less so when incomplete. The disease may progress over months to a year and tends to be self-limited in most cases. Some patients with the primary retinal form of SS may suffer recurrent episode of retinal vascular occlusion. Vision loss is typically experienced as partial and painless visual field loss in one or both eyes. Visual field loss unfortunately does not recover. The field defects are altitudinal and respect the horizontal meridian on visual field testing and uncommonly involve the blind spot. Funduscopy reveals branch retinal artery occlusion (BRAO). Hearing loss is cochlear and presents in one or both ears and frequently coincides initially with roaring tinnitus. Hearing loss is termed sensorineural when bone and air conduction are equal, and there is a wide degree of variability in severity. Severe loss may require cochlear implantation. At this time, there are no clinical or audiometric findings that are diagnostic for SS because sensorineural hearing loss occurs in other disease states. Hearing loss, however, remains part of the clinical triad. Cerebral involvement affects a number of areas, and a neuroimaging triad of white matter lesions, deep gray matter, lesions, and leptomeningeal disease is seen (4). Neurologic findings are based on location of the lesion and include mild memory impairment and psychosis when deep white matter is affected, ataxia with cerebellar involvement, hemiparesis with a more unilateral presentation, and diplopia with brainstem involvement. Late effects of SS after recovery may leave patients with spastic gait because of cerebral white matter disease rather than cervical cord disease given the rarity of this presentation (5). Since the initial descriptions of both clinical and neuroimaging triads, additional ophthalmic manifestations have Egan: J Neuro-Ophthalmol 2019; 39: 60-67 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review been recognized including Gass plaques (6) caused by local arterial wall damage and fluorescein staining that occurs in normal appearing retinal arterioles distant from involved vessels (7-15). Gass plaques (Fig. 1) and arterial wall hyperfluorescence on fluorescein angiography (FA) (Fig. 2) are emphasized in this report because they assist the clinician in confirming a diagnosis of SS. Some patients appear psychotic when encephalopathic and have skin changes resembling livedo reticularis (1). When bowel and bladder involvement is present in fulminant presentations, the clinician should search for cervical cord or cauda equina involvement (5,16,17). MRI (Fig. 3) and FA (Fig. 2) display unique findings and also have proven useful in establishing the diagnosis. These physical findings and clinical tests are complementary and some confirmatory in the diagnosis of SS when the clinical triad is incomplete. The pathophysiology of SS involves the endothelial cell that leads to infarction of target tissues. Injury to the endothelium is believed to be due to circulating antibodies, supported by studies of anti-endothelial cell antibodies (AECAs) (18-20). However, it is unknown whether these AECAs are causative or a result of local endothelial cell injury. Despite this lack of confirmation, practitioners treat patients suffering from SS with drugs that modify not only B cells but also T cells and with other more widespread targeted therapies. However, optimal treatment for this disorder remains unknown. METHODS A review of the literature from 1979 through 2017 was undertaken of the clinical findings of SS to determine those most indicative of the diagnosis. These include reviews of the fundus, FA, and MRI findings in patients with SS. The literature also was examined from 2000 through 2017 regarding various medications used to treat patients with SS, and then a treatment algorithm was proposed. Both literature reviews were conducted through PubMed and included foreign language journals. GASS PLAQUES The Gass plaque was first described by Gass et al, which was designated as retinal arterial wall plaques (RAWPs) (7). Multiple yellow RAWPs simulating emboli in 6 of 9 patients were detected with idiopathic BRAOs (8-10). It was concluded that Gass plaques were caused by a localized reaction, perhaps immune mediated, in the retinal artery wall and that the reaction might occasionally affect arteries in the inner ear and brain. These plaques were attributed to atheromatous deposits from slow extravasation of blood lipids into the arterial wall at the sites of arterial wall damage. Therefore, RAWPs are not true emboli, and the acronym was substituted by the eponym Gass plaque by John Susac, MD, in honor of the clinician who first described them. In 2003, the first description of Gass plaques in SS was made in 4 patients (6). They are round, yellow plaques that are located most commonly at midarteriolar segments and not at retinal bifurcations (Fig. 1). Furthermore, some patients reported with Gass plaques and recurrent BRAO may have had SS (7-10). Personal experience of Dr. Susac and this author indicate that Gass plaques in SS are very common in the FIG. 1. The left fundus of a 42-year-old woman with Susac syndrome shows 2 Gass plaques in a retinal arteriole along the inferotemporal arcade. Note that the plaques are not located at retinal arteriolar bifurcations. Egan: J Neuro-Ophthalmol 2019; 39: 60-67 61 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review RETINAL ARTERIOARTERIAL COLLATERALS FIG. 2. Fluorescein angiography of the left eye of a 26-yearold woman with Susac syndrome. There is staining of several retinal arterioles, which appeared normal on ophthalmoscopy, and the patient did not sustain a branch retinal artery occlusion. acute phase of the illness and can fluctuate with disease activity and then disappear. Because Gass plaques also are found in other disorders such as Eales disease and lymphoma, they are suggestive of SS but not pathognomonic of SS. Gass plaques are not seen on FA, only on funduscopy. For decades, retinal arterio-arterial (A-A) collaterals have been ascribed to BRAO (21-23). Review of the modern literature only found one more report of a 33-year-old man with bilateral BRAO and A-A collaterals that were ascribed to aortic valve disease because he had a calcific embolus in one fundus (24). There is a single case in the literature of A-A collaterals in SS (25) and another case in a review on diagnostic criteria in SS that shows a patient with collaterals although it cannot be determined in the photo if the collaterals are A-A or arteriovenous (26). In a recent report of 11 patients with SS where funduscopic photographs were available, 10 patients had collaterals of which 10 were A-A and 1 was arterio-venous (34). The location of the collaterals is approximately in the same area where arteriolar staining was previously found. These A-A collaterals are located more peripherally and not at the optic nerve head as with Nettleship collaterals. A literature search failed to identify a single patient with A-A collaterals away from the optic disc that were not associated with SS or cases suggestive of SS. This retinal finding strongly suggests the diagnosis of SS. These collaterals are not seen at initial presentation but develop later in the course of the disease. CENTRAL CALLOSAL LESIONS AND MRI Advances in neuroimaging with MRI have helped in the diagnosis of SS. The neuroimaging triad was first described in 2003 by Susac et al (4) and consists of white matter lesions, ARTERIOLAR WALL HYPERFLUORESCENCE FA is a useful tool in the evaluation of patients with SS. It is important in differentiating embolic from focal arterial wall damage in patients presenting with multiple BRAOs in one or both eyes. This arteriolar wall hyperfluorescence (AWH) can be seen at the site of infarction but also at the site of vessel wall damage where infarction has not yet occurred (Fig. 2). This was demonstrated in a patient with SS who 5 days later developed the characteristic BRAO in the abnormally staining vessel (11). Another patient with confirmed SS and AWH seen on FA was treated with tacrolimus, and the AWH resolved without retinal infarction (12). This was followed by several reports documenting findings of AWH in SS (13-15). Exact prevalence of the finding is unknown. Like Gass plaques, AWH on FA in a patient without the full clinical triad of SS should alert the practitioner to the diagnosis of SS, but unlike Gass plaques, the presence of AWH in normal appearing retinal arterioles is a pathognomonic feature of the syndrome. 62 FIG. 3. Sagittal T1 MRI displays a number of central corpus callosum lesions. Some have the appearance of a hole whereas others are elongated like spokes. Note that most do not touch the base of the corpus callosum. When these are found acutely, they will enhance following contrast administration. Egan: J Neuro-Ophthalmol 2019; 39: 60-67 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review deep gray matter lesions, and leptomeningeal enhancement. The most important point of the imaging study was that the corpus callosum was involved in all cases of SS (4). These callosal lesions are believed to be caused by infarction of tiny arterioles in the central part of the callosum causing the appearance of a "snowball" or "spoke," and over time will cavitate and develop the appearance of a hole (Fig. 3). This is similar to the T1 hole that develops in multiple sclerosis patients with periventricular white matter lesions. The location of these central callosal lesions also is different from the callosal lesions seen in multiple sclerosis because those tend to be more basal and likely are related to the different pathologies between these 2 disorders. SS has a strong predilection for the corpus callosum and involves this structure much more frequently than multiple sclerosis. Mildly affected patients tend to have only white matter involvement including the corpus callosum while severely affected patients have the full neuroimaging triad. Leptomeningeal enhancement is likely a marker of more fulminant disease activity. The central callosal lesion is another pathognomonic finding indicative of SS (3,4,27-29). LIVEDO RETICULARIS Livedo reticularis rarely is described in SS (30,31). It was seen in fulminant cases of SS with a cauda equina syndrome (16) but also noted in the initial description of the disease (1). Livedo may be seen in other disorders and can be seen in isolation and be idiopathic. Biopsy specimens of skin affected by livedo show platelet thrombi and a perivascular and intramural lymphocytic infiltrate (16). In 2014, through social media (Facebook), 479 patients were asked about different symptoms. There were 37 respondents and 8 (22%) complained of livedo during their active course (32). PSYCHOSIS The psychiatric manifestations of SS also are underemphasized. Many patients are paranoid at onset or have other psychiatric comorbidities. This was described in the initial report (1), and the first subject described with Gass plaques had numerous psychiatric admissions until his disease was stabilized (6). Also, it has been described as the presenting sign of the syndrome (33). Of the 37 respondents in the SS patient group, 17 (46%) reported paranoia during the course of their illness (32). TABLE 1. Diagnostic clinical triad of Susac syndrome Encephalopathy Low-frequency hearing loss in at least one ear BRAO in at least one eye BRAO, branch retinal artery occlusion. Egan: J Neuro-Ophthalmol 2019; 39: 60-67 TABLE 2. Diagnostic neuroimaging triad of Susac syndrome on MRI White matter lesions Gray matter lesions Leptomeningeal enhancement ANTI-ENDOTHELIAL CELL ANTIBODIES The site of injury in SS appears to be the endothelial cell. In the last 10 years, AECAs have been discovered and suggested as a diagnostic test in SS. The initial report documented a single patient who had AECAs in serum but not cerebrospinal fluid and titers of the antibodies decreased with glucocorticoid treatment (18). In another study of 10 women and 2 men, all had eye symptoms and 7 of 12 had encephalopathy (19). All but 2 had AECAs. A report of 20 patients with the full clinical triad of SS documented AECAs in only 25% (20). These AECAs are derived from the complement-activating IgGI subclass. Currently, it is unknown whether the antibodies are pathogenic or if they are an epiphenomenon that results from the pathophysiologic process of the disease. More research is required to determine the sensitivity and specificity of AECAs as well as matching antibodies to clinical phenotypes. Basing a diagnosis of SS on the presence of these antibodies is not recommended at this time. DIAGNOSTIC EVALUATION AND TREATMENT ALGORITHM Although diagnostic criteria for SS have been published (26), I have revised them for clinician usefulness. Clinicians can confirm the diagnosis of SS when patients have the full clinical triad (Table 1) or the neuroimaging triad (Table 2). During initial evaluation, all patients should have visual field testing, MRI, and FA. Audiograms should be obtained in patients complaining of hearing loss or tinnitus. When hearing loss is mild, low-frequency hearing loss is typically found, but when severe, all frequencies are affected. There are 2 imaging findings that make the diagnosis definite even when the clinical and neuroimaging triads are not fulfilled: (1) appearance of central callosal lesions on MRI and (2) AWH on FA in normal appearing retinal arterioles that are far removed from any BRAO (Table 3). In previously published criteria (26), a patient without the full clinical triad who presents with callosal lesions on MRI TABLE 3. Diagnostic isolated imaging findings of Susac syndrome Central callosal lesions on MRI AWH on FA remote from BRAO AWH, arterial wall hyperfluorescence; BRAO, branch retinal artery occlusion; FA, fluorescein angiography. 63 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review TABLE 4. Initial treatment of Susac syndrome Start corticosteroids Start IVIg monthly for 6 months For breakthrough disease, add mycophenolate mofetil and/ or rituximab For breakthrough disease after adding mycophenolate mofetil and rituximab, add cyclophosphamide IVIg, intravenous immunoglobulin. or AWH on FA, the diagnosis was probable SS. I believe that this is incorrect. Given the discussion above, the presence of a central callosal lesion is confirmatory of definite SS. Furthermore, the description of AWH is too vague because it includes any location of AWH. However, AWH at the site of a BRAO is nonspecific; AWH located away from a BRAO is confirmatory for definite SS. This distinction regarding the location of the AWH is very important. Currently, the best treatment for patients with SS is not known. Despite the "belief" that SS is a B cell- mediated disease, patients have been treated with B and well as T cell therapies with success. A review of the literature provides many different paradigms for treatment that include various combinations of drugs: corticosteroids, intravenous immunoglobulin (IVIg), mycophenolate mofetil, azathioprine, methotrexate, cyclophosphamide, and rituximab. Also, there are monoclonal antibodies that have been released or will soon be released that show promise, specifically natalizumab, ocrelizumab, alemtuzumab, daclizumab, and adalimumab. Between 2000 and 2017, there were 63 articles published that included a treatment algorithm for patients with SS (3,14,17,19,20,25,29,30,33,35-86). The most commonly documented medication was IVIg found in 30 reports followed by some type of corticosteroid. Twentytwo reports described usage of cyclophosphamide and only 6 with rituximab and 5 with mycophenolate mofetil. A single article regarding natalizumab indicated an exacerbation of disease after treatment (35). I am aware of several patients treated with success for their SS with natulizumab (John Susac, MD, deceased, Winter Haven, FL; Ilka Kleffner, MD, Munster, Germany; personal communication). With the large number of anecdotal reports in the literature and personal experience, a number of recommendations can be made (Table 4). All patients with active SS should be started on corticosteroids and IVIg. Corticosteroids may be given as prednisone orally at 80 mg a day or intravenous methylprednisolone 1,000 mg a day and then switched to oral prednisone after several days of intravenous treatment. IVIg should be started initially at 2 g/kg over several days and then given monthly at 0.4 mg/kg every month for a total of 6 months before a decision is made to consider cessation of treatment. Both medications are 64 TABLE 5. Ongoing treatment guidelines for Susac syndrome Therapy is inadequate if there are new or enhancing lesions on MRI Therapy is inadequate if there are new visual field defects, and FA shows AWH remote from BRAO Therapy is adequate and should be maintained if there are no new or enhancing lesions on MRI, and there are no new visual field defects even if FA shows AWH remote from BRAO Therapy can be stopped or reduced if there are no new or enhancing lesions on MRI, no new visual field defects, and no AWH on FA AWH, arterial wall hyperfluorescence; BRAO, branch retinal artery occlusion; FA, fluorescein angiography. ideal due to rapid onset of action. Lack of treatment with IVIg in the first 6 months tends to allow for relapses especially when the retina is primarily affected. If a patient is breaking through on this initial dual therapy, mycophenolate mofetil and/or rituximab should be added. Mycophenolate mofetil typically is dosed at 500 mg twice a day for a week and then increased to 1,000 mg twice a day. Rituximab is initiated as a single dose of 500 mg given once and then repeated in 6 months. Some practitioners may give rituximab 250 mg once then repeated in 2 weeks followed by 500 mg every 6 months and some may treat with slightly higher doses. The large number of reports in the literature strongly suggests that cyclophosphamide is effective in SS but, given its side effect profile, I recommend that this be added only after treatment failures with previous medications. Antiplatelet drugs and anticoagulants are ineffective in SS. After initial diagnosis, the patient should be reassessed at 1 month and again at 3 months with visual field testing, MRI, and FA (Table 5). These tests should always be performed if the patient complains of new symptoms. An audiogram may be repeated if the patient complains of new hearing loss. Medical management is inadequate if there is any disease activity on MRI denoted by active enhancing lesions. Therapy also is inadequate if there is a new visual field defect and AWH in FA. FA is very sensitive for detecting disease activity, and patients can tolerate some AWH as long as visual field testing is stable and not deteriorating. With these findings, maintenance therapy should be continued. When the MRI is inactive, FA is inactive, and visual fields are stable, the patient can be considered in remission and one of the drugs can be withdrawn. The patient should be followed closely for any disease recurrence, and gradually, each drug can be discontinued until the patient is off all therapy. Patients with disease that primarily affects the retina may have difficulty getting off of IVIg because this drug is very effective at preventing retinal relapses. Egan: J Neuro-Ophthalmol 2019; 39: 60-67 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review CONCLUSIONS SS is a rare disorder but may be more common than once thought. Diagnosis is often delayed because of lack of recognition of clinical and neuroimaging findings. A definite diagnosis of SS can be made when the clinical triad or the neuroimaging triad is present. Two pathognomonic findings in SS are the presence of central callosal lesions on MRI and AWH on FA remote from a BRAO. When either of these signs is present, the diagnosis of SS is definite. The presence of Gass plaques should strongly suggest the diagnosis of SS although they do not make the diagnosis definite. Patients also may exhibit livedo reticularis, psychosis, or retinal A-A collaterals. More research on AECAs needs to be performed to determine their clinical utility. Corticosteroids and IVIg are the mainstay of initial therapy and mycophenolate mofetil, and/or rituximab should be added for breakthrough therapy. 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