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NeuroCure Clinical Research Centre, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany (J. Dörr, S. Krautwald, F. Paul). Division of Molecular Neuroimmunology, Department of Neurology, University Hospital Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany (B. Wildemann, S. Jarius). Department of Neurology, Heinrich-Heine-University, Medical Faculty, Moorenstrasse 5, 40225 Düsseldorf, Germany (M. Ringelstein, O. Aktas). Department of Neurology, University of Münster, Albert-Schweitzer-Strasse 33, 48129 Münster, Germany (T. Duning, E. B. Ringelstein, I. Kleffner).

Correspondence to: J. Dörr jan-markus.doerr@charite.de

Characteristics of Susac syndrome: a review of all reported casesJan Dörr, Sarah Krautwald, Brigitte Wildemann, Sven Jarius, Marius Ringelstein, Thomas Duning, Orhan Aktas, Erich Bernd Ringelstein, Friedemann Paul and Ilka Kleffner

Abstract | In Susac syndrome, occlusions of microvessels—presumed to be mediated by an autoimmune response to an as yet unknown antigen—lead to a characteristic clinical triad of CNS dysfunction, branch retinal artery occlusions, and sensorineural hearing impairment. Susac syndrome is considered a rare but important differential diagnosis in numerous neurological, psychiatric, ophthalmological, and ear, nose and throat disorders. Improved understanding of this disorder is crucial, therefore, to ensure that patients receive appropriate treatment and care. Current knowledge on Susac syndrome is largely based on reports of single patients, small case series, and nonsystematic reviews. The aim of this Review is to extend these previous, primarily anecdotal findings by compiling data from all 304 cases of Susac syndrome that have been published worldwide, which were identified following a literature search with predefined search, inclusion and exclusion criteria. From this data, we present an overview of demographic, clinical and diagnostic data on Susac syndrome, providing a reliable basis for our current understanding of this rare disease. Where possible, we make recommendations for clinical diagnosis, differential diagnosis, and management of patients with suspected Susac syndrome.

Dörr, J. et al. Nat. Rev. Neurol. advance online publication 30 April 2013; doi:10.1038/nrneurol.2013.82

IntroductionSusac syndrome is a rare disorder that is thought to be caused by autoimmune-mediated occlusions of microvessels in the brain, retina and inner ear. These occlusions lead to a characteristic clinical triad of CNS dysfunction, visual disturbances due to branch retinal artery occlusions (BRAO), and hearing defi-cits.1–3 Typical findings in patients with Susac syndrome include demonstration of BRAO on retinal fluorescein angio graphy (Figure 1a), characteristic, predominantly callosal lesions on cranial MRI (Figure 1b,c),4,5 and evi-dence of sensori neural hearing loss. The eponym was coined by John O. Susac in 1979,6 but the first reports of patients with this disorder were made in 1973.7,8 Notably, the disease has also been referred to as ‘small infarctions of cochlear, retinal and encephalic tissue’ (SICRET) syndrome9–11 and ‘microangiopathy with retinopathy, encephalopathy and deafness’ (RED-M).12,13

Since the first descriptions of Susac syndrome in the 1970s, numerous reports of single patients with this disorder and small case series—occasionally includ-ing complementary data from nonsystematic reviews of the literature—have been published. Few of these studies involved more than four patients.5,14–20 Given the lack of systematic data on Susac syndrome, our current knowledge on the epidemiology, clinical presentation

spectrum, disease course, paraclinical findings, prognosis and treatment options for this disorder largely rests upon non systematic and anecdotal data. Data are vague with regard to age and gender differences, clinical patterns of presentation, clinical significance of cerebro spinal fluid (CSF) changes, and findings of brain biopsies. Despite its presumed rarity, Susac syndrome is considered as a differential diagnosis in various neurological, psychiat-ric and ophthalmological disorders, as well as ear, nose and throat (ENT) conditions (Box 1).2 Indeed, Susac syndrome is often misdiagnosed as multiple sclerosis (MS).4,14,21–23 A need remains, therefore, for better char-acterization of Susac syndrome. Whereas therapeutic approaches and prognosis should ideally be addressed in prospective clinical trials, reliable epi demiological, clinical and paraclinical data can be derived through review and evaluation of existing literature.

The aim of this Review is to summarize data from all reported cases of Susac syndrome. Through application of predefined criteria (Supplementary Box 1 online), 164 publications reporting on 304 individual patients with Susac syndrome were identified (Supplementary Table 1 online).1,2,5–15,17–20,23–165 From the data reported in these studies, we provide an overview of the demographics, clinical presentation, and outcome of diagnostic pro-cedures in patients with Susac syndrome. Where possi-ble, recommendations for clinical diagnosis, differential diagnosis, and management of patients with suspected Susac syndrome are made. Improved understanding of this rare disorder could eventually enable establishment

Competing interestsJ. Dörr declares an association with the following company: Novartis Pharma. See the article online for full details of the relationship. The other authors declare no competing interests.

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of consensus criteria for diagnosis and management of individuals with Susac syndrome.

Demographic data Geographical locationSince the first reports of Susac syndrome in the 1970s,6–8 the number of published cases has steadily increased. Cases from all continents have been described, although the majority of reports have been from North America and Europe (152 and 126 patients, respectively; Supplementary Table 1 online). Data on ethnicity were provided in only 25% of the reports analysed, but most published cases were of white individuals (Table 1).

Sex differencesThe incidence of Susac syndrome is reported to be higher in females than in males. Previously reported estimates of male:female ratio are variable, however, ranging from exclusively female cases in early reports to 1:3 and 1:5.5 in more recent publications.9,14,17 Analysis of demo-graphic data from all available Susac syndrome cases reveals a male:female ratio of 1:3.5 (Table 1). Given that data on gender were provided in all 304 patients analy-sed, this ratio can be considered a reliable estimation. As autoimmunity is generally more common in females

than in males, female predominance in Susac syndrome is in line with the putative autoimmune aetiology of this disease.2,19,120,166

On the basis of data from more than 275 patients (Supplementary Table 1 online), the typical age at disease onset can also be reliably defined. 81% of first clinical manifestations were reported in patients between 16 and 40 years of age, with most individuals (59%) being aged between 21 and 35 years at disease onset. No statistically significant difference was observed between males and females with regard to age of onset. Notably, eleven cases of Susac syndrome (5% of female patients) occurred in the context of pregnancy: seven during pregnancy15,28,33,44,63,112,143,146,150 and four in the postpartum period.15,17,26,114

Clinical courseRennebohm et  al.22 suggest empirical stratifica-tion of Susac syndrome into three major clinical courses—namely, monocyclic, polycyclic and chronic– continuous—with an active period lasting ≤2 years being the critical parameter that separates the mono cyclic course from the polycyclic and chronic–continuous forms. Classification of patients on the basis of this para-digm was possible in 114 cases (Supplementary Table 1 online); the reported follow-up time in the remaining cases was too short for unambiguous classification. Of the classifiable patients, 54% had monocyclic disease—defined as fluctuating disease that self-limits after a maximum period of 2 years and does not recur—and 42% had polycyclic disease with relapses that continued beyond a 2-year period (Table 1). As only four patients (4%) developed the chronic–continuous form,24,36,132,143 future prospective studies are required to determine whether this third category is of clinical relevance and/or practical value in diagnosis of Susac syndrome.

In female patients, monocyclic and polycyclic disease courses were equally distributed (n = 44 and n = 43, respectively). In male patients, however, monocyclic disease was more common than polycyclic disease (n = 18 versus n = 5, P = 0.017). Patients with monocyclic disease were slightly older at disease onset than were

Key points

■ Susac syndrome is a rare but important differential diagnosis in numerous neurological, psychiatric, ophthalmological, and ear, nose and throat disorders

■ On the basis of data obtained from 304 published cases, the mean age of onset of Susac syndrome is estimated at 31.6 years, with a male-to-female ratio of 1:3.5

■ Presentation with the full clinical triad of symptoms (CNS, eye and ear symptoms) at disease onset is rare and, therefore, diagnosis should not rely solely on presence of the triad

■ Presence of oligoclonal bands and/or intrathecal IgG does not exclude a diagnosis of Susac syndrome, but lack of both signs remains an important criterion for differentiation from multiple sclerosis

■ Invasive diagnostic procedures such as brain biopsy or cerebral angiography do not aid establishment of a diagnosis of Susac syndrome, so should be reserved for exceptional cases

■ The role of antibodies targeting endothelial cells in the pathophysiology and diagnosis of Susac syndrome remains to be determined

a cb

Figure 1 | Fluorescein angiography and MRI findings in Susac syndrome. a | Retinal fluorescein angiography of the left eye in a 33-year-old female patient with active disease who reported visual field deficits. Characteristic branch retinal artery occlusion (large arrows) with leakage of fluorescence dye (small arrow) is evident. b,c | Sagittal T1-weighted (b) and T2-weighted (c) cranial MRI (at 7 Tesla) of a 33-year-old male patient (patient #3 from Wuerfel et al.164) showing characteristic lesions in the corpus callosum (arrow). Strong hypointense signal on the T1-weighted image indicates severe tissue destruction. Part a is courtesy of R. Bergholz, Charité-Universitätsmedizin, Berlin, Germany.

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patients with polycyclic disease (mean 31.3 years versus 27.2 years, P = 0.013), but this observation is probably of minor clinical relevance. Across all cases examined, average duration of the active phase was 21 months (ranging from 1 to 252 months), with approximately 2.4 relapses experienced per patient (Table 1). The longest disease-free period between two relapses was 18 years.167

Clinical presentationClinical manifestations of Susac syndrome occur at first onset and during the course of disease (Table 2). The finding that only 13% of patients with available data had the characteristic clinical triad of Susac syndrome at disease onset is of high clinical importance as it dis-proves the theory that first presentation of Susac syn-drome always involves concomitant appearance of CNS manifestation, ear involvement and BRAO. Indeed, the average delay between first symptoms and completeness of the triad was 21 weeks. The assumption that presence of the triad is needed for a definitive diagnosis of Susac syndrome is presumably a major cause of misdiagnosis.

Interestingly, presentation with the complete triad at onset was more common in patients with a monocyclic course (n = 11; 18% of all cases with available data) than in those with polycyclic disease (n = 1; 2% of all cases with available data), which suggests that patients with a mono-cyclic disease course are more likely to present with the full triad. Cautious interpretation is advisable, however, for various reasons. For example, observation of the triad was twice as common in male patients (n = 11; 20% of male patients with available data) than in female patients (n = 20; 10% of female patients with available data). Furthermore, the number of patients with complete triad at onset and with a polycyclic course was low and, as stated above, monocyclic disease was more common in males than females. Against the background of a need for early and sufficient treatment, the finding that presence of the com-plete triad at disease onset is rare leads to two conclusions. First, diagnosis of Susac syndrome solely on the basis of the presence of the complete triad may not be appropri-ate. Second, a targeted search for absent components of the triad, such as subtle retinal or ENT manifestations in patients with encephalopathy, is essential.

At clinical onset, the most common manifestation was CNS symptoms (observed in two-thirds of patients), followed by visual symptoms and hearing disturbances (Table 2). Headaches were present at disease onset in about 80% of patients with available data (Table 2), often resembled migraine-like headaches, and were more fre-quent in patients with CNS manifestations than in those without such features (84% versus 60%, P <0.001).

During disease (mean obser vat ion per iod: 41 ± 46 months), the complete triad was documented in 85% of cases with available data. The remaining 15% of cases were interpreted as incomplete Susac syndrome, had an incomplete diagnostic workup, or were not sufficiently described (Supplementary Table 1 online). Neurological, ophthalmological and ENT manifestations occurred at similar proportions in most cases during disease (Table 2). Specific clinical manifestations were considered only if

reported in more than 5% of all cases examined (Table 3). Encephalopathy—characterized by cognitive impairment (mainly deficits of memory, concentration and execu-tive functions) or confusion and/or disorientation—and hearing loss were the most frequent clinical manifesta-tions (reported in 76% and 86% of cases, respectively; Table 3). Encephalopathy seems to be more common in

Box 1 | Differential diagnoses of Susac syndrome1,2

Inflammatory demyelinating CNS diseaseMultiple sclerosis, acute disseminated encephalomyelitis, neuromyelitis optica (Devic disease)

Cerebrovascular diseaseStroke, transient ischaemic attack, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

Vasculitis, connective tissue disease or other autoimmune diseasesPrimary CNS vasculitis, limbic encephalitis, polyarteritis nodosa, Wegener granulomatosis, Churg–Strauss syndrome, systemic lupus erythematosus, sarcoidosis, Sjögren syndrome, Behçet disease, antiphospholipid antibody syndrome, Cogan syndrome, Eales disease, autoimmune inner-ear disease

Infectious CNS diseaseLyme disease, syphilis, tuberculosis, viral encephalitis

MalignancyPrimary CNS lymphoma, CNS metastases, paraneoplastic syndrome

OthersMigraine, encephalopathy, lactate acidosis and stroke-like episodes (MELAS), Menière disease, psychotic disorders (including drug-related psychosis), isolated branch retinal artery occlusion

Table 1 | Demographic data from studies of Susac syndrome

Demographic feature

Cases with available data* (% of total cases)

Description Number of cases (% of cases with available data) or time

Gender 304 (100) MaleFemale

67 (22)237 (78)

Ethnicity 76 (25) WhiteAfrican-AmericanAsianHispanicTurkish

61 (81)3 (4)6 (8)2 (1)4 (5)

Age at disease onset

276 (91) Mean ± SDRange

31.6 ± 10.4 years8–65 years

Disease course 114 (37) MonocyclicPolycyclicChronic continuous

62 (54)48 (42)4 (4)

Active disease period

192 (63) Mean ± SDRange

21 ± 37 months1–252 months

Number of relapses 201 (66) Mean ± SDRange

2.4 ± 1.81–10

Length of follow-up 234 (77) Mean ± SDRange

41 ± 46 months1–252 months

*For further details of the studies from which data were obtained, see Supplementary Table 1 online.

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the monocyclic form (86%) than in polycyclic disease (71%), a finding that supports previous observations.22 Although occasionally reported, seizures occurred in only 4% of Susac syndrome cases and should not, therefore, be considered a key feature of disease.

Manifestations of Susac syndrome other than the classic presentations have also been highlighted. For example, myalgia and/or arthralgia were reported in nine cases,13,30,44,56,58,76,82,128 and clinically evident der-matological signs (mainly livedo reticularis) were observed in 13 cases.6,13,26,30,44,58,60,76,83,134,144,145 Infection prior to first onset of disease was reported in 19 cases,11,13,14,26,29,44,55–57,60,86,123,128,141,151,158,162 suggesting that an infectious trigger of disease is unlikely. The clinical relevance of these nonclassical presentations is unclear, but such features may warrant prospective investigations.

Diagnostic proceduresMain diagnostic proceduresDetermination of which procedures are necessary to estab-lish a diagnosis of Susac syndrome is an important issue. MRI, retinal fluorescein angiography, and audio metry are considered crucial tests to enable diagnosis (Figure 1). Information on the outcomes for these diagnostic proce-dures are reported in many—but not all—of the 304 pub-lished cases of Susac syndrome (Table 4 and Supplementary Table 1 online). Presence of pathology in patients with sus-pected Susac syndrome was more often documented using MRI, fluorescein angiography, and audiometry testing (Table 4) than symptoms being clinically evident (Table 3). For example, 170 patients reported visual dysfunction during the course of the disease, whereas BRAO detected using fluorescein angio graphy was reported in 217 patients. This finding indicates that subclinical pathology occurs in a substantial number of patients without clinical manifesta-tion, and further emphasises the importance of an appro-priate inter disciplinary diagnostic workup in patients with suspected Susac syndrome.

Fluorescein angiography and audiometryThe fact that BRAO was detected in 99% of patients for whom fluorescein angiography data were available high-lights the importance of this procedure in the diagnostic workup of suspected Susac syndrome cases. Notably, fluorescein angiography should be considered even if the patient does not report visual disturbances. Audiometry reports (when documented) revealed sensorineural hearing loss, more commonly bilateral than unilateral, in almost every patient. In most cases, the low to midtone range of hearing was affected. Fluorescein angiography and audiometry procedures should be performed in

Table 2 | Clinical presentations at onset and during disease course

Symptoms Manifestation at onset Manifestation during disease course

Number of cases with available data (% of total cases)

Reported cases (% of cases with available data)

Number of cases with available data (% of total cases)

Reported cases (% of cases with available data)

Complete triad* 247 (81) 31 (13) 297 (98) 252 (85)

CNS involvement‡ 247 (81) 165 (67) 300 (99) 274 (91)

Eye involvement§ 248 (82) 99 (40) 301 (99) 293 (97)

Ear involvement 248 (82) 91 (37) 300 (99) 288 (96)

Headaches 182 (60) 141 (78) 196 (65) 171 (87)

*Concomitant clinical involvement of CNS (excluding asymptomatic MRI abnormalities), eye (including asymptomatic branch retinal artery occlusion), and ear. ‡Excludes asymptomatic MRI abnormalities. §Includes asymptomatic branch retinal artery occlusion.

Table 3 | Clinical manifestations of Susac syndrome

Manifestation Reported cases (% of total cases)

Comments

CNS

EncephalopathyCognitive impairment

ConfusionEmotional disturbanceBehavioural changesPersonality changesApathyPsychosisReduction of vigilance

230 (76)146 (48)

119 (39)48 (16)46 (15)36 (12)35 (12)29 (10)26 (9)

—Usually loss of memory, concentration and executive functionsOften involving disorientation————Often paranoiaSeverity can range from lightheadedness to coma

Ataxia 77 (25) Excludes gait ataxia

Vertigo 75 (25) —

Gait abnormality 72 (24) Mainly gait ataxia

Sensory disturbance 73 (24) Includes tingling, dysaesthesia and numbness

Upper motor neuron signs 63 (21) Includes extensor plantar response, spasticity and hyperreflexia

Paresis 62 (20) —

Nausea and vomiting 45 (15) —

Dysarthria 40 (13) —

Oculomotor dysfunction 29 (10) Includes any kind of nystagmus, ophthalmoplegia and saccadic ocular pursuit

Urinary dysfunction 27 (9) Mostly urgency; possibly related to encephalopathy, but can occur without overt encephalopathy

Diplopia 20 (7) —

Eye

Visual disturbance 170 (56) Any visual symptoms, including blurring, flashing and scintillation

Ear

Tinnitus 88 (29) —

Hearing loss 260 (86) —

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every case as early as possible during the course of the disease, as even normal findings can provide important information for evaluation of subtle changes in these measures during follow-up.

MRISupratentorial white matter lesions on T2-weighted cranial MRI were reported in almost all 204 patients with available MRI data (Supplementary Table 1 online) but, in general, specificity of white matter lesions for diagnosis is low. More detailed information on the location of the brain lesions was reported in 64% of all cases examined (Figure 2). Involvement of the corpus callosum—in par-ticular, evidence of ‘snowball lesions’—is considered a characteristic sign of Susac syndrome4 and was found in all patients with this disorder in a previous MRI study.5 Collective analysis of the available case studies, however, revealed callosal lesions in only 160 of 204 (78%) patients with available MRI data, although existing lesions may not have been documented, and lesions might have developed only later in the disease course. Collectively, the evidence suggests that lack of callosal involvement, although not sufficient to exclude a diagnosis of Susac syndrome, should lead the clinician to question this diagnosis.

Interestingly, restitution of brain lesions was reported in some studies.38,75,103 This feature might be helpful in particular cases, such as for differentiation from multi-ple sclerosis—a disease in which extensive restitution of T2-hyperintense lesions is not a typical feature. Despite some clinical evidence for spinal cord involvement in Susac syndrome,2 no spinal cord lesions have been identified on MRI of patients with Susac syndrome. Few reports provided sufficient MRI data on brain atro-phy,5,14,55,69,77,93,123,149,161,164 but findings from these studies suggest that atrophy, particularly of the corpus callosum, may be prominent in patients with Susac syndrome.5,164

Additional diagnostic proceduresIn patients with suspected Susac syndrome, diagnos-tic procedures in addition to those described above are often performed, including comprehensive screening for autoantibodies and clotting abnormalities, CSF analysis, EEG, cerebral catheter angiography (CAA), and lepto-meningeal biopsy (Table 4). Whether such tests can provide clinically relevant information remains unclear.

Autoantibodies and clotting abnormalitiesOf 181 patients for whom data were available, 41 had sero-logical or clotting abnormalities. A mild elevation of anti-nuclear antibody (ANA) titre was evident in 22 of these individuals (7% of total patients).15,20,28,31,33,35,44–46,76,89,116,120,146,162 Notably, however, this proportion corresponds to the fre-quency of individuals in the healthy population who have high ANA titres, and suggests that detection of elevated ANA is not relevant to the diagnosis of Susac syndrome.168 Elevation of a blood-clotting protein, factor VIII, has been suggested as a finding of potential pathophysiological rele-vance in Susac syndrome,16,166 but was reported in only nine patients.20,44,91,98,103,112,132 Antiendothelial cell antibodies (AECA), also hypothesized to be of pathophysiological

Table 4 | Diagnostic data from identified cases of Susac syndrome

Diagnostic finding Number of cases with available data (% of total cases)

Number of reported cases (% of available cases)

MRI 204 (67)

Supratentorial white matter lesions 199 (98)

Supratentorial grey matter lesions 83 (42)

Infratentorial lesions 86 (43)

Focal enhancement* 149 (49) 76 (51)

Leptomeningeal enhancement* 146 (48) 33 (23)

Visual acuity 116 (38)

Normal 34 (29)

Reduced 82 (71)

Visual field 167 (55)

Normal 4 (2)

Scotoma 163 (98)

Retinal fluorescein angiography 219 (72)

Normal 2 (1)

Branch retinal artery occlusion* 217 (99)

Arterial wall hyperfluorescence 83 (27) 80 (96)

Audiometry 213 (70)

Normal 9 (4)

Unilateral sensorineural deficit 57 (27)

Bilateral sensorineural deficit 147 (69)

EEG* 86 (28)

Normal 14 (16)

Diffuse slowing 49 (57)

Focal dysrhythmia 18 (21)

Epileptic activity 5 (6)

Cerebrospinal fluid

Pleocytosis (≥ 5 cells/μl) 209 (69) 93 (45)

Protein elevation (>0.5 g/l) 207 (68) 173 (84)

Abnormal serum glucose (>50%) 109 (36) 0

Abnormal lactate (>2.2 mmol/l) 15 (5) 0

Dysfunction of blood–brain barrier 34 (11) 10 (29)

IgG synthesis 86 (28) 13 (15)

Oligoclonal bands 129 (42)

CSF-restricted 5 (4)

Non-CSF-restricted 5 (4)

Digital subtraction angiography 103 (34)

Normal 99 (96)

Pathological 4 (4)

Brain biopsy 35 (12)

Normal 4 (11)

Abnormal 31 (83)

Vasculitis and clotting abnormalities‡ 181 (60)

Normal 140 (77)

Pathological 41 (23)

*Observed or examined at any time point. ‡For details see main text; antiendothelial antibodies not included. Abbreviation: CSF, cerebrospinal fluid.

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relevance in Susac syndrome, were detected in eleven patients, but this feature was investigated in only three studies that collectively involved 14 patients.120,112,19 Based on the findings described above, broad screening for autoantibodies or clotting abnormalities is dispensable in patients with suspected Susac syndrome, unless required for differential diagnostic purposes.

Cerebrospinal fluid analysisModerate elevation of protein (to a mean of 1.62 g/l) was the most common CSF finding across all Susac syndrome cases, observed in 84% of cases with available CSF data. Elevated protein in the CSF occurred either in isola-tion or in combination with a mild and usually lympho-cytic pleocytosis (median 12 cells/μl), the latter of which was reported in 45% of patients with available CSF data. Compared with cases that lacked CNS involvement, protein elevation was more common in patients with CNS involve-ment (86% versus 42%, P <0.001), as was pleo cytosis (46% versus 17%, P = 0.046). Neither para meter differed with regard to presence of BRAO or ENT symptoms. Presence of pleocytosis was independent of disease course, whereas protein elevation in the CSF was more common in those with a monocyclic disease course than in individuals with a polycyclic disease course (90% versus 69%, P = 0.01). Additional routine CSF parameters were also investigated in some cases (Table 4); although reports on these measures were too infrequent to enable estimation of their true value, they could be useful in the differential diagnostic work up. Notably, reported data on CSF tests are possibly confounded by the fact that lumbar puncture is likely to be more readily performed in cases with CNS involvement, and this fact should be considered during interpretation of these studies.

Previous studies suggest that presence of oligoclonal bands (OCBs) is not a sign of Susac syndrome.14,55,93

Although data on isoelectric focusing were provided for only 129 cases, OCBs were reported in five patients as CSF-restricted (OCB pattern type 2 according to an inter national consensus classification169),20,39,44,132,141 and in another five cases as non-CSF-restricted but with similar serum bands (OCB pattern type 3 or 4).20,50,57,102,119 Qualitative evidence for intrathecal IgG synthesis was doc-umented in 15% of patients with definite Susac syndrome and available CSF data. Presence of OCBs and/or intra-thecal IgG synthesis, therefore, does not necessarily enable exclusion of a diagnosis of Susac syndrome. Nevertheless, OCB status remains an important parameter for differen-tiation of Susac syndrome from MS—a disease in which isolated OCBs are found in up to 98% of patients.170,171

Other proceduresEEG findings in patients with suspected Susac syn-drome, although often showing poor specificity, can indicate the presence of encephalopathy (Table 4). CCA was performed in a substantial number of patients, but most studies reported normal findings: only four of 103 patients examined with CCA had temporary stenoses of the middle cerebral artery.9,14,24,25 As the vessels affected in Susac syndrome are too small to be depicted on CCA, this procedure should be reserved for special cases—for example, when cerebral vasculitis is suspected. When performed, brain biopsy revealed focal micro-angiopathic and/or gliotic changes in the majority of cases (28 of 35 patients). Subtle perivascular infiltrates were described in eight cases, leptomeningeal infiltra-tions in three cases, and arteriolar wall thickening in another eight case reports. Four histological samples were described as normal.83,119,128,138 Remarkably, overt demyelination was not reported in any cases.

Data limitationsThe key characteristics of Susac syndrome described above were extrapolated from available data on cases of this dis-order. Several limitations to this approach should be noted.

First, only data from published cases were considered. These cases may not be representative of Susac syndrome in general, and publication bias towards cases with par-ticular findings or with severe forms of disease cannot be excluded. Single cases could have been missed if not rep-resented in the databases searched; given the large number of patients included, however, such additional cases would be unlikely to substantially influence the overall findings. Some cases have been repeatedly published, for example to illustrate different aspects of the disease.

The completeness of data provided in the literature presents another issue: whereas some reports are compre-hensive, others are short or were published exclusively as abstracts—a format in which the data are often incomplete. Information on gender, age, and some MRI parameters were almost always provided, whereas reports on para-meters such as ethnicity were fragmented (Supplementary Table 1 online). This variability in reporting will inevitably lead to variability in the validity of data. To address this issue and provide a rough guide to data reliability, the number of cases with available data is presented where possible.

78%

Corp

us

callo

sum Pe

ri-

vent

ricula

rBa

sal

gang

lia

Cere

bellu

m

Lesion location

Num

ber

of r

epor

ted

case

s

Subc

orte

x

Thala

mus

Brain

stem

0

160

120

80

40

20

180

100

60

140

Cent

rum

semiov

ale

Cere

bella

r

pedu

ncles

Deep whit

e

matte

rInt

erna

l

caps

ule Corte

x

9%11%14%15%

17%

23%24%25%28%

66%

3%

Figure 2 | Location of brain lesions in patients with Susac syndrome. Graph shows number of Susac syndrome cases with lesions at each brain location, as observed on MRI. Percentages are based on data from 204 patients from whom imaging data were available (64% of all cases examined).

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Therapy response and prognosis, although important aspects of Susac syndrome (Box 2), are not discussed in this Review for a number of reasons: first, treatment strategies varied considerably and reporting of treatment details (such as dose, frequency and duration) was vari-able; second, treatment responses were not captured in a standardized fashion; and third, therapeutic response is too critical a measure to be evaluated retrospectively on the basis of anecdotal reports. These issues should instead be addressed in well-designed prospective studies.

Classification of disease course presents another meth-odological issue. In this Review, we used the most widely accepted classification system, proposed by Rennebohm et al. in 2008.22 This approach has limitations in the context of evaluation of case reports, however, as assign-ment of cases to one of the three major courses is possi-ble only after a documented follow-up of at least 2 years. As information reported in case studies often provides only a ‘snapshot’ of information, the number of evaluable cases was inevitably low.

Last, with regard to pooled analyses (for example, in CSF analysis), one should consider that differ-ent laboratories use different quantification methods and protein standards. Such variability in technical approach can limit comparability and, thus, validity of the collective findings.

ConclusionsOn the basis of data derived from 304 published indi-vidual cases of Susac syndrome, this Review provides a systematic analysis of demographic, clinical and diag-nostic features of the disorder. Although a rare disease, improved understanding of Susac syndrome is of clinical relevance as it is an important differential diagnosis in numerous neurological, psychiatric, ophthalmo logical and ENT disorders, and is often mis diagnosed.2,14,22 Aside from important demographic findings (Table 1), three observations made in this Review merit closer attention.

First, the majority of patients who were eventually diagnosed with Susac syndrome did not initially present with the complete triad of symptoms, and the mean delay between the first symptom and the completion of the triad was approximately 5 months. Consequently, to wait for appearance of the full triad before establish-ing the diagnosis and starting necessary treatment will not always be appropriate. However, Susac syndrome is rare, and uncritical overuse of the diagnosis should be avoided. An appropriate approach would be to perform a targeted search for absent components of the triad if the clinical presentation is suggestive of Susac syndrome, followed by application and assessment of validated diagnostic criteria.

Second, despite a substantial number of patients being subjected to invasive diagnostic procedures such brain biopsy or cerebral angiography, in many cases these pro-cedures did not aid the diagnosis. We suggest, therefore, that in patients with a clinical presentation suggestive of Susac syndrome, audiometry and retinal fluorescein angiography should be performed before potentially harmful procedures are carried out.

Third, detection of autoantibodies—particularly AECA—in some patients with Susac syndrome might indicate involvement of autoantibodies in the patho-genesis of the disease, and tests for this feature could have potential as a diagnostic tool. Given that only a small number of patients have been investigated for the presence of autoantibodies, systematic screening for anti-bodies such as AECA in a large and well-characterized cohort of patients with definite Susac syndrome will be necessary to further understand their role in disease.

Finally, systematic data on treatment strategies are urgently needed. As data derived from prospective therapeutic trials are unlikely to be available in the near future, standardized documentation of treatment para-digms, treatment responses, and long-term outcomes represents a more feasible and pragmatic approach. Such documentation, together with improved under-standing of the presentation of Susac syndrome, will prevent misdiagnosis and ensure that patients receive best possible care.

Box 2 | Empirical treatment strategies in Susac syndrome

Prospective or randomized controlled trials of treatments for Susac syndrome do not exist owing to the rarity of this disorder and the lack of knowledge on its pathogenesis. Empirical treatment strategies are based on the hypothesis of an autoimmune inflammatory endotheliopathic aetiology,19,112,120 signs of inflammation in brain biopsies and cerebrospinal fluid,44,166 and on the reports of good response to immunosuppressive and immunomodulatory therapy in single case reports and case series.1,2,14,15,17,44,56,95,103,123,146,150 Expert recommendations are based on experience of treatment of juvenile dermatomyositis—an autoimmune disease that has some characteristics in common with Susac syndrome.22,172 Treatment comprises aggressive multimodal immunosuppressive therapy in the acute period, with high doses of corticosteroids, cyclophosphamide, methotrexate, azathioprine and/or mycophenolate mofetil, and intravenous immunoglobulins. After the acute period, treatment should be continued for several months up to 2.5 years, with a slow tapering of corticosteroids. Alternative drugs, such as rituximab, etanercept or cyclosporine A, are recommended in refractory cases. According to one case series, plasmapheresis may be a useful adjunct or alternative therapy for patients who do not improve following steroid treatment.15 Single reports demonstrate improvement or stabilization in response to rituximab when combined with other immunosuppressive drugs,15,150 and inhibition of tumour necrosis factor with the drug infliximab was reported to be beneficial in a single patient.146 To reduce the risk of thrombosis of the small arterioles, antiplatelet or anticoagulant therapy is sometimes recommended.17,172 Nimodipine has also been recommended.37 Given that Susac syndrome is frequently misdiagnosed as MS, a single case observation of exacerbation of Susac syndrome upon treatment with IFN-β is noteworthy.23 Patients with severe hearing loss may benefit from cochlear implants.22

Review criteria

We searched PubMed and EMBASE for articles published up to December 2012 using the following terms: “Susac syndrome OR Susac’s syndrome”, “SICRET”, “RED-M”, “microangiopathy AND encephalopathy AND retinopathy”, “encephalopathy AND retinal artery occlusion”, “hearing loss AND retinal artery occlusion” (all fields); “brain AND retina AND cochlea”, “retina AND brain AND inner ear”, “microangiopathy AND brain AND retina” (titles/abstracts); “brain AND eye AND ear”, “retinopathy AND encephalopathy” (titles). For further details and information on inclusion and exclusion criteria, see Supplementary Box 1 online. Reference lists of identified articles were screened for additional reports. Articles in Chinese, English, German, French, Spanish or Portuguese were considered.

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AcknowledgementsJ. Dörr and F. Paul are supported by the German Research Foundation (DFG Exc 257).

Author contributionsJ. Dörr, S. Krautwald, B. Wildemann, S. Jarius, M. Ringelstein, T. Duning, O. Aktas, E. B. Ringelstein and F. Paul researched data for the article. J. Dörr, B. Wildemann, S. Jarius, M. Ringelstein, T. Duning, O. Aktas, E. B. Ringelstein, P. Friedemann and I. Kleffner provided substantial contributions to discussion of content. J. Dörr wrote the article. All authors provided substantial contribution to review and/or editing of the manuscript before submission.

Supplementary information is linked to the online version of the paper at www.nature.com/nrneurol.

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